Thiocarbamate derivatives as a2a inhibitors, pharmaceutical composition thereof and combinations with anticancer agents

ABSTRACT

The present invention relates to thiocarbamate derivatives of Formula (I) which are useful as A2A adenosine receptor (A2AR) inhibitors 
     
       
         
         
             
             
         
       
     
     Especially, the present invention relates to a pharmaceutical composition comprising an A2A inhibitor of Formula (I) and a lipid carrier such as lauroyl macrogol-32 glycerides, D-α-tocopherol-polyethylene glycol-1000 succinate or a mixture thereof. The pharmaceutical composition of the invention is particularly useful for oral dosing in the treatment of cancers. 
     The present invention also relates to a combination comprising an A2A receptor inhibitor of Formula (I) and an anticancer agent. The anticancer agent is for example an immunotherapeutic agent, such as a checkpoint inhibitor. The invention further relates to a pharmaceutical composition and a kit of parts comprising such combination. Additionally, the combination of the invention is particularly useful for the treatment and/or prevention of cancers.

FIELD OF INVENTION

The present invention relates to thiocarbamate derivatives which areuseful as A2A adenosine receptor (A2AR) inhibitors.

Especially, the present invention relates to a pharmaceuticalcomposition comprising a thiocarbamate derivative as adenosine A2Areceptor inhibitor. The pharmaceutical composition of the invention isparticularly useful for oral dosing in the treatment of cancers.

The present invention also relates to a combination comprising an A2Aadenosine receptor (A2AR) inhibitor and an anticancer agent. The A2ARinhibitor is a thiocarbamate derivative of Formula (I) as defined below.The anticancer agent is for example an immunotherapeutic agent, such asfor example a checkpoint inhibitor. The invention further relates to apharmaceutical composition and a kit of parts comprising suchcombination. The combination of the invention is particularly useful forthe treatment and/or prevention of cancers.

SEQUENCE LISTING

The instant application contains a Sequence Listing which has been filedelectronically in ASCII format and is hereby incorporated by referencein its entirety. Said ASCII copy, created on Jun. 1, 2022, is namedIST-006D1_Sequence_Listing.txt and is 1,401 bytes in size.

BACKGROUND OF INVENTION

Many of the immunosuppressive mechanisms in tumors are common tophysiological immunoregulation in normal tissues. Such immunoregulationis very important in keeping the immune system under control in order toblock a self-reactive immune response and to prevent an ongoing immuneresponse from causing critical tissue damage. The lack of physiologicalimmunoregulation often results in overwhelming immune activation thataccompanies autoimmunity. For example, CTLA-4 is a physiologicalmechanism that negatively regulates T cell activity by blocking acostimulatory signal through CD28-B7 interaction. The lack of CTLA4causes non-specific T cell activation, and CTLA-4-deficient mice die inseveral weeks with massive lymphocytic tissue infiltration. PD-1 alsoprovides a T cell inhibitory signal upon interaction with its ligands,PD-L1 and PD-L2. Deficiency of PD-1 in mice is known to cause varioustypes of autoimmune disorders depending on the genetic strains.

Besides cell surface transducers of immunosuppressive signal, e.g.,CTLA-4 and PD-1, immunosuppression in the tumor microenvironmentinvolves anti-inflammatory cytokines (IL-10, TGF-β), enzymes(indoleamine-2,3-dioxygenase), and professional immunoregulatory cells(regulatory T cells, myeloid-derived suppressor cells MDSCs). Theseimmunosuppressive mechanisms play an important role in controllingimmune response in normal tissues. Since tumors take advantage of suchphysiological immunoregulatory mechanisms to protect their tissue fromimmune attack, these mechanisms intended to prevent inflammatorycomplication, now turn out to be major obstacles hampering spontaneouscancer regression and immunological cancer treatment. The identificationof immunosuppressive mechanisms in tumors pointed out molecular targetsto restore the antitumor immune response. Thus, these negativeimmunoregulatory mechanisms, so-called immune checkpoints, became afocus in drug discovery. Antibodies against PD1, PDL1 or CTLA4 have beenapproved as anticancer therapies on a large number of indications, suchas Metastatic Melanoma, Non-Small Cell Lung Cancer, Renal CellCarcinoma, Hodgkin's Lymphoma, Head and Neck Cancer, UrothelialCarcinoma, Hepatocellular Carcinoma, as well as treatment of forpatients with solid tumors that have one of two specific geneticfeatures known as mismatch repair deficiency and high microsatelliteinstability (irrespective of cancer type).

Extracellular adenosine has been known as an inhibitor of immunefunctions. While intracellular adenosine is involved in energymetabolism, nucleic acid metabolism, and the methionine cycle,extracellular adenosine plays an important role in intercellularsignaling. Its signal is transmitted by G protein-coupled adenosinereceptors on the cell surface, and it affects diverse physiologicalfunctions including neurological, cardiovascular, and immunologicalsystems.

Tumors contain high levels of extracellular adenosine, suggesting thattumor cells may benefit from its immunosuppressive effect and catabolicenergy production (Allard et al., Curr. Opin. Pharmacol., 2016, 29,7-16; Otta A., Frontiers in Immunology, 2016, 7: 109). This high levelof extracellular adenosine is probably due to overexpression of theenzyme CD73, which is responsible for production of extracellularadenosine. CD73 is overexpressed by a large number of tumors, with allthe following tumors expressing medium or high levels of CD73 in >50% oftumor surface by immunohistochemistry (www.proteinatlas.org): Breast,Carcinoid, Cervical, Colorectal, Endometrial, Glioma, Head and Neck,Liver, Lung, Melanoma, Ovarian, Pancreatic, Prostate, Renal, Gastric,Thyroid, Urothelial.

Of the four known types of adenosine receptors, A2A adenosine receptor(A2AR) is the predominantly expressed subtype in most immune cells.Stimulation of A2AR generally provides an immunosuppressive signal thatinhibits activities of T cells (proliferation, cytokine production,cytotoxicity), NK cells (cytotoxicity), NKT cells (cytokine production,CD40L upregulation), macrophages/dendritic cells (antigen presentation,cytokine production), and neutrophils (oxidative burst). The presence ofhigh levels of extracellular adenosine in tumors was found to play asignificant role in the evasion of antitumor immune response.Especially, it was shown that A2AR-deficient mice could spontaneouslyregress the inoculated tumor, whereas no wild-type mice showed similartumor regression. A2AR antagonists were also beneficial in tumor-bearingwild-type animals. Importantly, depletion of T cells and NK cellsimpaired the retardation of tumor growth by A2AR antagonists, suggestingimprovement of antitumor cellular immune response. Effector functions ofT cells and NK cells are susceptible to A2AR stimulation. In addition,when activated in the presence of A2AR agonist, the effector function ofT cells is persistently impaired even after removal of A2AR agonist.This result suggests that the adenosine-rich environment in tumors mayinduce T cells that are anergic to the tumor cells.

Therefore, given that A2A receptor is expressed in most immune cells andparticularly effector immune cells such as T cells and NK cells andgiven that A2A receptor is engaged in tissues where adenosine isproduced, it is thought that A2A inhibitors can be helpful in all thecancer indications.

Consequently, there is a need for A2A inhibitors able to restore immunefunctions in tumors environment.

Adenosine is known to be an endogenous modulator of a number of otherphysiological functions. For example, at the central nervous system(CNS) level, adenosine in known to induce sedative, anxiolytic andantiepileptic effects level.

Thus, A2A inhibitors were previously developed for the treatment ofdepression and neurodegenerative diseases such as Parkinson's disease orAlzheimer's disease (Pinna A., CNS Drugs, 2014, 28, 455). One of themost advanced A2A inhibitors developed for the treatment of CNS diseasesis Preladenant (Hodgson R A et al., J. Pharmacol. Exp. Ther., 2009,330(1), 294-303; Hauser R A et al., JAMA Neurol., 2015, 72(12),1491-500).

However, such previously developed A2A inhibitors were designed to crossthe blood brain barrier, in order to target A2A receptor in the CNS.

Given the higher level of adenosine in tumors when compared to thebrain, much higher amounts of compounds will be needed to achieve thedesired effect on immune functions restoration for treating cancers.Thus, in order to avoid deleterious side effects, one should provide A2Ainhibitors which have a limited, if any, CNS penetrance, contrary to allpreviously developed A2A inhibitors.

The Applicant provided a series of non-brain penetrant A2A inhibitors ininternational patent application PCT/EP2018/058301, being thiocarbamatederivatives, which are useful to restore immune functions in tumorenvironment.

Nevertheless, these compounds present a very low solubility in aqueousbuffers, a low intestinal solubility and thus a low oralbioavailability. Consequently, there is a need for a pharmaceuticalformulation of these compounds that would be suitable for oraladministration.

As evidenced in the experimental part below, the Applicant herebyprovides a pharmaceutical composition that enables suitable oralbioavailability of the thiocarbamates A2A inhibitors.

Further, the anticancer effect of anticancer agents, such as for exampleimmunotherapeutic agents, chemotherapeutic agents or antiangiogenicagents or combinations thereof, may remain insufficient. This is may bedue, at least in part, to tumors immune escape mechanisms as thosedescribed above.

The specific combination of A2AR inhibitors (especially thethiocarbamate derivatives disclosed in WO2018/178338) with otheranticancer agents has not been reported. Herein, the Applicant providesa combination comprising an adenosine A2A receptor inhibitor asdisclosed in WO2018/178338 and another anticancer agent, for example animmunosuppressive agent such as a checkpoint inhibitor.

SUMMARY

This invention thus relates to a pharmaceutical composition comprising:

-   -   (a) a compound of Formula (I) as defined hereafter or a        pharmaceutically acceptable salt or solvate thereof;

-   -   (b) a liquid carrier selected from lauroyl polyoxyl-32        glycerides, D-α-tocopherol-polyethylene glycol-1000 succinate        and mixtures thereof, and    -   (c) optionally one or more other pharmaceutically acceptable        carrier, diluent, excipient and/or adjuvant.

In one embodiment, the compound of Formula (I) is of the subformulaedefined below, especially Formulae (Ia), (Ia-1), (Ia-1a), (Ia-1b),(Ia-1c) or (Ia-1d). In one embodiment, the compound of Formula (I) isone of those listed in Table 1 below. In a specific embodiment, thecompound of Formula (I) is selected from:

-   (R,S)-5-amino-3-(2-(4-(2,4-difluoro-5-(2-(methylsulfinyl)ethoxy)phenyl)piperazin-1-yl)ethyl)-8-(furan-2-yl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one;-   (+)-5-amino-3-(2-(4-(2,4-difluoro-5-(2-(methylsulfinyl)ethoxy)phenyl)piperazin-1-yl)ethyl)-8-(furan-2-yl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one;    -   and pharmaceutically acceptable salts or solvates thereof.

In one embodiment, the compound of Formula (I) is under the form of asalt, wherein the salt is the hydrochloride or esylate salt.

In one embodiment, the pharmaceutical composition of the inventionfurther comprises PEG 400 and/or PEG 3350. In one embodiment, thepharmaceutical composition of the invention, further comprises caprylicacid.

In one embodiment, the pharmaceutical composition of the inventionfurther comprises an antioxidant, which is may be for example butylatedhydroxytoluene (BHT).

In one embodiment, the pharmaceutical composition of the inventionfurther comprises a wetting agent; preferably the wetting agent isselected from sodium lauryl sulphate, vitamin E TPGS, sodium docusate,polysorbate 80 and poloxamer 407; more preferably the wetting agent issodium lauryl sulphate.

In one embodiment, the pharmaceutical composition of the invention,further comprises a precipitation inhibitor; preferably theprecipitation inhibitor is selected from hydroxypropylmethylcellulose,methylcellulose, polyvinylpyrrolidone, polyvinylpyrrolidonepolyvinylacetate copolymer, polyvinyl caprolactam-polyvinylacetate-polyethylene glycol graft copolymer and poloxamer 407; morepreferably hydroxypropylmethylcellulose.

In one embodiment, in the pharmaceutical composition of the invention,the compound of Formula (I) is present in an amount ranging from 1% to20% w/w, preferably from 5% to 15% w/w, more preferably about 10% w/w.

In one embodiment, in the pharmaceutical composition of the invention,the lipid carrier is present in an amount ranging from 55% to 99% w/w,preferably from 60% to 95% w/w, more preferably from 70% to 90% w/w.

In one embodiment, the pharmaceutical composition of the invention canbe formulated as capsules, tablets or granules. In one embodiment, whenthe pharmaceutical composition of the invention is formulated ascapsules, the capsule shells are constructed from gelatin and whereinadditional components are optionally included in the capsule shells,such as for example polyethylene glycol and sodium lauryl sulphate.

The present invention further relates to a method of treating cancer,comprising administering to a patient in need thereof a therapeuticallyacceptable effective amount of a pharmaceutical composition according tothe invention. In one embodiment, the cancer is selected from breast,carcinoid, cervical, colorectal, endometrial, glioma, head and neck,liver, lung, melanoma, ovarian, pancreatic, prostate, renal, gastric,thyroid and urothelial cancers.

This invention thus relates to a combination comprising:

-   -   (a) at least one a compound of Formula (I):

-   -   -   or a pharmaceutically acceptable salt or solvate thereof,            wherein R¹ and R² are as defined below; and

    -   (b) at least one anticancer agent.

In one embodiment, the compound of Formula (I) is of Formula (Ia),(Ia-1) or (Ia-1b) as defined below. In one embodiment, the compound ofFormula (I) is one of those listed in Table 1 below.

In one embodiment, the anticancer agent is selected fromimmunotherapeutic agents, chemotherapeutic agents, antiangiogenicagents, multidrug resistance-associated proteins inhibitors,radiotherapeutic agents, and any combination thereof.

In one embodiment, the immunotherapeutic agent is selected fromcheckpoint inhibitors, checkpoint agonists, IDO inhibitors, PI3Kinhibitors, adenosine receptor inhibitors, adenosine-producing enzymesinhibitors, CD40 agonists, IL2 variants, immune cells, therapeuticvaccines, or any combination thereof.

In one embodiment, the checkpoint inhibitor is an inhibitor of acheckpoint protein selected from PD-1, PD-L1, CTLA-4 and TIGIT.

In one embodiment, the inhibitor of PD-1 is an anti-PD-1 antibody; theinhibitor of PD-L1 is an anti-PD-L1 antibody; the inhibitor of CTLA-4 isan anti-CTLA-4 antibody, and the inhibitor of TIGIT is an anti-TIGITantibody.

In one embodiment, the chemotherapeutic agent is selected fromanticancer alkylating agents, anticancer antimetabolites, anticancerantibiotics, plant-derived anticancer agents, anticancer platinumcoordination compounds, Parp inhibitors, anti-hormone-sensitive canceragents and any combination thereof. In one embodiment, the anticancerantibiotic is doxorubicin. In one embodiment, the anticancer platinumcoordination compound is oxaliplatin. In one embodiment, the combinationof chemotherapeutic agents is selected from (i) a combination consistingof folinic acid, fluorouracil and oxaliplatin; (ii) a combinationconsisting of carboplatin and paclitaxel; and (iii) a combinationconsisting of gemcitabine and nab-paclitaxel.

In one embodiment, the combination of the invention comprises at leastone compound of Formula (I) as herein defined and at least twoanticancer agents as herein defined.

The invention also relates to a pharmaceutical composition comprising:

-   -   (a) at least one compound of Formula (I) as herein defined; and    -   (b) at least one anticancer agent as herein defined.

The invention further relates to a kit of parts comprising:

-   -   (a) a first part comprising at least one compound of Formula (I)        as herein defined; and    -   (b) a second part comprising at least one anticancer agent as        herein defined.

In one embodiment, the combination, the pharmaceutical composition orthe kit of parts according to the invention are for medical use.

In one embodiment, the combination, the pharmaceutical composition orthe kit of parts according to the invention are for use in the treatmentand/or prevention of cancer.

In one embodiment, the cancer is selected from breast, carcinoid,cervical, colorectal, endometrial, glioma, head and neck, liver, lung,melanoma, ovarian, pancreatic, prostate, renal, gastric, thyroid andurothelial cancers.

In one embodiment, the constituents of the combination, or of the kit ofparts according to the invention are to be administered to a patient inneed thereof sequentially and/or concurrently.

In one embodiment, the constituents of the combination, or of the kit ofparts according to the invention are to be administered to a patient inneed thereof via different administration routes.

Definitions

In the present invention, the following terms have the followingmeanings:

The term “aldehyde” refers to a group —CHO.

The term “alkenyl” refers to unsaturated hydrocarbyl group, which may belinear or branched, comprising one or more carbon-carbon double bonds.Suitable alkenyl groups comprise between 2 and 6 carbon atoms,preferably between 2 and 4 carbon atoms, still more preferably between 2and 3 carbon atoms. Examples of alkenyl groups are ethenyl, 2-propenyl,2-butenyl, 3-butenyl, 2-pentenyl and its isomers, 2-hexenyl and itsisomers, 2,4-pentadienyl and the like.

The term “alkenylcarbonyl” refers to a group —(C═O)-alkenyl whereinalkenyl is as herein defined.

The term “alkenylcarbonylamino” refers to a group —NH—(C═O)-alkenylwherein alkenyl is as herein defined.

The term “alkoxy” refers to a group —O-alkyl wherein alkyl is as hereindefined.

The term “alkyl” refers to a hydrocarbyl radical of formulaC_(n)H_(2n+1) wherein n is a number greater than or equal to 1.Generally, alkyl groups of this invention comprise from 1 to 8 carbonatoms, more preferably, alkyl groups of this invention comprise from 1to 6 carbon atoms. Alkyl groups may be linear or branched. Suitablealkyl groups include methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyland octyl.

The term “alkylaminoalkyl” refers to a group -alkyl-NH-alkyl whereinalkyl is as herein defined.

The term “alkylaminoalkylaminocarbonyl” refers to a group—(C═O)—NH-alkyl-NH-alkyl wherein alkyl is as herein defined.

The term “(alkylaminoalkyl)(alkyl)aminocarbonyl” refers to a group—(C═O)—NR¹R² wherein R¹ is an alkyl group and R² is a -alkyl-NH-alkylgroup, wherein alkyl is as herein defined.

The term “alkylaminoalkylcarbonyl” refers to a group—(C═O)-alkyl-NH-alkyl wherein alkyl is as herein defined.

The term “alkylcarbonyl” refers to a group —(C═O)-alkyl wherein alkyl isas herein defined.

The term “alkylheteroaryl” refers to any heteroaryl substituted by analkyl group wherein alkyl is as herein defined.

The term “alkyloxycarbonyl” refers to a group —(C═O)—O-alkyl whereinalkyl is as herein defined.

The term “alkylsulfonyl” refers to a group —SO₂-alkyl wherein alkyl isas herein defined.

The term “alkylsulfonealkyl” refers to a group -alkyl-SO₂-alkyl whereinalkyl is as herein defined.

The term “alkylsulfonimidoyl” refers to a group —S(═O)(═NH)-alkylwherein alkyl is as herein defined.

The term “alkylsulfoxide” refers to a group —(S═O)-alkyl wherein alkylis as herein defined.

The term “alkylsulfoxidealkyl” refers to a group -alkyl-SO-alkyl whereinalkyl is as herein defined.

The term “alkyne” refers to a class of monovalent unsaturatedhydrocarbyl groups, wherein the unsaturation arises from the presence ofone or more carbon-carbon triple bonds. Alkynyl groups typically, andpreferably, have the same number of carbon atoms as described above inrelation to alkyl groups. Non-limiting examples of alkynyl groups areethynyl, 2-propynyl, 2-butynyl, 3-butynyl, 2-pentynyl and its isomers,2-hexynyl and its isomers—and the like.

The term “alkynealkyl” refers to a group -alkyl-alkyne wherein alkyl andalkyne are as herein defined.

The term “amino” refers to a group —NH₂.

The term “aminoalkyl” refers to a group -alkyl-NH₂ wherein alkyl is asherein defined.

The term “aminoalkylaminocarbonyl” refers to a group —(C═O)—NH-alkyl-NH₂wherein alkyl is as herein defined.

The term “aminoalkylcarbonylamino” refers to a group —NH—(C═O)-alkyl-NH₂wherein alkyl is as herein defined.

The term “aminocarbonyl” refers to a group —(C═O)—NH₂.

The term “(aminocarbonylalkyl)(alkyl)amino” refers to a group —NR¹R²wherein R¹ is an alkyl group and R² is a -alkyl-(C═O)—NH₂ group, whereinalkyl is as herein defined.

The term “aminocarbonylalkylamino” refers to a group —NH-alkyl-(C═O)—NH₂wherein alkyl is as herein defined.

The term “aminosulfonyl” refers to a group —SO₂—NH₂.

The term “antioxidant” refers to an agent that diminishes or avoids theoxidation of other substances.

The term “aryl” refers to a polyunsaturated, aromatic hydrocarbyl grouphaving a single ring (i.e. phenyl) or multiple aromatic rings fusedtogether (e.g. naphtyl), typically containing 5 to 12 atoms; preferably5 to 10; more preferably the aryl is a 5- or 6-membered aryl.Non-limiting examples of aryl comprise phenyl, naphthalenyl.

The term “carbonyl” refers to a group —(C═O)—.

The term “carbonylamino” refers to a group —NH—(C═O)—.

The term “cycloalkyl” refers to a cyclic alkyl group, that is to say, amonovalent, saturated, or unsaturated hydrocarbyl group having 1 or 2cyclic structures. Cycloalkyl includes monocyclic or bicyclichydrocarbyl groups. Cycloalkyl groups may comprise 3 or more carbonatoms in the ring and generally, according to this invention comprisefrom 3 to 10, more preferably from 3 to 8 carbon atoms; still morepreferably more preferably the cycloalkyl is a 5- or 6-memberedcycloalkyl. Examples of cycloalkyl groups include but are not limited tocyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl.

The term “cycloalkyloxy” refers to a group —O-cycloalkyl whereincycloalkyl is as herein defined.

The term “dialkylamino” refers to a group —NR¹R² wherein R¹ and R² areboth independently alkyl group as herein defined.

The term “dialkylaminoalkyl” refers to a group -alkyl-NR¹R² wherein R¹and R² are both independently alkyl group, as herein defined.

The term “dialkylaminoalkylaminocarbonyl” refers to a group—(C═O)—NH-alkyl-NR¹R² wherein R¹ and R² are both alkyl group, as hereindefined.

The term “dialkylaminoalkylcarbonyl” refers to a group—(C═O)-alkyl-NR¹R² wherein R¹ and R² are both alkyl group, as hereindefined.

The term “dihydroxyalkyl” refers to a group alkyl is as herein definedsubstituted by two hydroxyl (—OH) groups.

The term “halo” or “halogen” refers to fluoro, chloro, bromo, or iodo.

The term “heteroaryl” refers to an aryl group as herein defined whereinat least one carbon atom is replaced with a heteroatom. In other words,it refers to 5 to 12 carbon-atom aromatic single rings or ring systemscontaining 2 rings which are fused together, typically containing 5 to 6atoms; in which one or more carbon atoms is replaced by oxygen, nitrogenand/or sulfur atoms where the nitrogen and sulfur heteroatoms mayoptionally be oxidized and the nitrogen heteroatoms may optionally bequaternized. Non-limiting examples of such heteroaryl, include:oxazolyl, thiazolyl, imidazolyl, furanyl and pyrrolyl. Preferably theheteroaryl is a 5- or 6-membered heteroaryl, more preferably the 5- or6-membered heteroaryl is a furyl.

The term “heterocyclyl” refers to non-aromatic, fully saturated orpartially unsaturated cyclic groups (for example, 3 to 7 membermonocyclic, 7 to 11 member bicyclic, or containing a total of 3 to 10ring atoms) which have at least one heteroatom in at least one carbonatom-containing ring. Preferably the heterocyclyl is a 5- or 6-memberedheterocyclyl. Each ring of the heterocyclic group containing aheteroatom may have 1, 2, 3 or 4 heteroatoms selected from nitrogenatoms, oxygen atoms and/or sulfur atoms, where the nitrogen and sulfurheteroatoms may optionally be oxidized and the nitrogen heteroatoms mayoptionally be quaternized. The heterocyclic group may be attached at anyheteroatom or carbon atom of the ring or ring system, where valenceallows. The rings of multi-ring heterocycles may be fused, bridgedand/or joined through one or more spiro atoms. Non limiting exemplaryheterocyclic groups include aziridinyl, oxiranyl, thiiranyl,piperidinyl, azetidinyl, 2-imidazolinyl, pyrazolidinyl imidazolidinyl,isoxazolinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl,isothiazolidinyl, piperidinyl, succinimidyl, 3H-indolyl, indolinyl,isoindolinyl, 2H-pyrrolyl, 1-pyrrolinyl, 2-pyrrolinyl, 3-pyrrolinyl,pyrrolidinyl, 4H-quinolizinyl, 2-oxopiperazinyl, piperazinyl,homopiperazinyl, 2-pyrazolinyl, 3-pyrazolinyl, tetrahydro-2H-pyranyl,2H-pyranyl, 4H-pyranyl, 3,4-dihydro-2H-pyranyl, oxetanyl, thietanyl,3-dioxolanyl, 1,4-dioxanyl, 2,5-dioximidazolidinyl, 2-oxopiperidinyl,2-oxopyrrolodinyl, indolinyl, tetrahydropyranyl, tetrahydrofuranyl,tetrahydrothiophenyl, tetrahydroquinolinyl, tetrahydroisoquinolin-1-yl,tetrahydroisoquinolin-2-yl, tetrahydroisoquinolin-3-yl,tetrahydroisoquinolin-4-yl, thiomorpholin-4-yl,1-oxido-1-thiomorpholin-4-yl, 1-dioxido-1-thiomorpholin-4-yl,1,3-dioxolanyl, 1,4-oxathianyl, 1,4-dithianyl, 1,3,5-trioxanyl,1H-pyrrolizinyl, tetrahydro-1,1-dioxothiophenyl, N-formylpiperazinyl,and morpholin-4-yl.

The term “heterocyclylalkylaminocarbonyl” refers to a group—(C═O)—NH-alkyl-heterocyclyl, wherein alkyl and heterocyclyl are asherein defined.

The term “(heterocyclyl)(alkyl)aminoalkyl” refers to a group-alkyl-NR¹R² wherein R¹ is an alkyl group and R² is a heterocyclylgroup, wherein alkyl and heterocyclyl are as herein defined.

The term “heterocyclylcarbonyl” refers to a group —(C═O)-heterocyclylwherein heterocyclyl is as herein defined.

The term “heterocyclylalkyl” refers to a group -alkyl-heterocyclylwherein alkyl and heterocyclyl are as herein defined.

The term “heterocyclyloxy” to a group —O-heterocyclyl whereinheterocyclyl is as herein defined.

The term “heterocyclylsulfonyl” refers to a group —SO₂-heterocyclylwherein heterocyclyl is as herein defined.

The term “hydroxyalkyl” refers to a group -alkyl-OH wherein alkyl is asherein defined.

The term “hydroxyalkylaminoalkyl” refers to a group -alkyl-NH-alkyl-OHwherein alkyl is as herein defined.

The term “hydroxycarbonyl” refers to a group —C(═O)—OH wherein carbonylis as herein defined. In other words, “hydroxycarbonyl” corresponds to acarboxylic acid group.

The term “oxo” refers to a ═O substituent.

The term “sulfonylamino” refers to a group —NH—SO₂.

The term “about”, preceding a figure encompasses plus or minus 10%, orless (such as plus or less 1%), of the value of said figure. It is to beunderstood that the value to which the term “about” refers is itselfalso specifically, and preferably, disclosed.

The term “administration”, or a variant thereof (e.g. “administering”),means providing the active agent or active ingredient (e.g. an A2ARinhibitor or an anticancer agent), alone or as part of apharmaceutically acceptable composition, to the patient in whom/whichthe condition, symptom, or disease is to be treated or prevented.

The term “autologous” refers to any material derived from the sameindividual to whom it is later to be re-introduced.

The term “allogenic” refers to any material derived from a differentindividual of the same specie as the individual to whom the material isintroduced. Two or more individuals are said to be allogenic to oneanother when the genes at one or more loci are not identical.

In some aspects, allogenic material from individuals of the same speciesmay be sufficiently unlike genetically to interact antigenically.

The terms “IC₅₀” or “half maximal inhibitory concentration” representthe concentration of an inhibitor that is required for 50% inhibition invitro.

The term “inhibitor” refers to a natural or synthetic compound that hasa biological effect to inhibit or significantly reduce or down-regulatethe expression of a gene and/or a protein or that has a biologicaleffect to inhibit or significantly reduce the biological activity of aprotein. Consequently, an “A2AR inhibitor” refers to a compound that hasa biological effect to inhibit or significantly reduce or down-regulatethe biological activity of A2A receptor.

The term “human” refers to a subject of both genders and at any stage ofdevelopment (i.e. neonate, infant, juvenile, adolescent, adult).

The term “patient” refers to a warm-blooded animal or a mammal, morepreferably a human, who/which is awaiting the receipt of, or isreceiving medical care or is/will be the object of a medical procedure.

The expression “pharmaceutically acceptable” refers to the ingredientsof a pharmaceutical composition are compatible with each other and notdeleterious to the subject to which it is administered.

The expression “pharmaceutically acceptable carrier, diluent, excipientand/or adjuvant” refers to a substance that does not produce an adverse,allergic or other untoward reaction when administered to an animal,preferably a human. It includes any and all inactive substances such asfor example solvents, cosolvents, antioxidants, surfactants, stabilizingagents, emulsifying agents, buffering agents, pH modifying agents,preserving agents (or preservating agents), antibacterial and antifungalagents, isotonifiers, granulating agents or binders, lubricants,disintegrants, glidants, diluents or fillers, adsorbents, dispersingagents, suspending agents, coating agents, bulking agents, releaseagents, absorption delaying agents, sweetening agents, flavoring agentsand the like. For human administration, preparations should meetsterility, pyrogenicity, general safety and purity standards as requiredby regulatory offices, such as, e.g., FDA Office or EMA.

The term “predrug”, as used herein, means any compound that will bemodified to form a drug species, wherein the modification may take placeeither inside or outside of the body, and either before or after thepredrug reaches the area of the body where administration of the drug isindicated.

The terms “prevent”, “preventing” and “prevention”, as used herein,refer to a method of delaying or precluding the onset of a condition ordisease and/or its attendant symptoms, barring a patient from acquiringa condition or disease, or reducing a patient's risk of acquiring acondition or disease.

The term “prodrug” as used herein means the pharmacologically acceptablederivatives of compounds of Formula (I), such as for example esters oramides, whose in vivo biotransformation product generates thebiologically active drug. Prodrugs are generally characterized byincreased bio-availability and are readily metabolized into biologicallyactive compounds in vivo.

The terms “therapeutically effective amount” or “therapeuticallyeffective dose” refer to the amount or dose of active ingredient that isaimed at, without causing significant negative or adverse side effectsto the subject, (1) delaying or preventing the onset of a cancer in thesubject; (2) reducing the severity or incidence of a cancer; (3) slowingdown or stopping the progression, aggravation, or deterioration of oneor more symptoms of a cancer affecting the subject; (4) bringing aboutameliorations of the symptoms of a cancer affecting the subject; or (5)curing a cancer affecting the subject. A therapeutically effectiveamount may be administered prior to the onset of a cancer for aprophylactic or preventive action. Alternatively, or additionally, atherapeutically effective amount may be administered after initiation ofa cancer for a therapeutic action.

The terms “treating” or “treatment” refer to therapeutic treatment;wherein the object is to prevent or slow down the targeted pathologiccondition or disease. A subject or mammal is successfully “treated” fora disease or affection or condition if, after receiving the treatmentaccording to the present invention, the subject or mammal showsobservable and/or measurable reduction in or absence of one or more ofthe following: reduction of the number of cancer cells; and/or relief tosome extent, for one or more of the symptoms associated with thespecific disease or condition; reduced morbidity and mortality, andimprovement in quality of life issues. The above parameters forassessing successful treatment and improvement in the disease arereadily measurable by routine procedures familiar to a physician.

The term “subject” refers to a mammal, preferably a human. In oneembodiment, the subject is diagnosed with a cancer. In one embodiment,the subject is a patient, preferably a human patient, who/which isawaiting the receipt of, or is receiving, medical care or was/is/will bethe subject of a medical procedure or is monitored for the developmentor progression of a disease, such as a cancer. In one embodiment, thesubject is a human patient who is treated and/or monitored for thedevelopment or progression of a cancer. In one embodiment, the subjectis a male. In another embodiment, the subject is a female. In oneembodiment, the subject is an adult. In another embodiment, the subjectis a child. The terms “tumor-specific antigen” or “tumor-associatedantigen” refer to an antigen specifically and/or abundantly expressed bycancer cells or tumor cells. T cells expressing T cell receptorsrecognizing and binding said antigens may be referred to as T cellsrecognizing a tumor-specific or tumor-associated antigen, T cellsspecific for a tumor-specific or tumor-associated antigen, T cellsspecific of a tumor-specific or tumor-associated antigen, or T cellsdirected to a tumor-specific or tumor-associated antigen. The term“vaccine” refers to a preparation comprising a substance or a group ofsubstances (i.e., a vaccine) meant to induce and/or enhance in a subjecta targeted immune response towards an infectious agent (such as viruses,bacteria, fungi or parasites) or towards cancer cells. Prophylacticvaccination is used to prevent a subject from ever having a particulardisease or to only have a mild case of the disease. Therapeuticvaccination is intended to treat a particular disease in a subject. Forexample, therapeutic anti-cancer vaccines may comprise atumor-associated antigen or tumor-associated antigens, aiming atinducing and/or enhancing a cell-mediated immune response, in particulara T cell immune response, directed towards the cancer cells expressingsaid tumor-associated antigen(s).

DETAILED DESCRIPTION

A2AR Inhibitor

The present invention relates to pharmaceutical compositions andcombinations of anticancer agents comprising at least one A2A adenosinereceptor (A2AR) inhibitor. The A2AR inhibitor is a thiocarbamatederivative, especially a thiocarbamate derivative as those disclosed inPCT/EP2018/058301. More preferably the A2AR inhibitor is a thiocarbamatederivative of formula (I) as described below.

In one embodiment, the thiocarbamate derivative A2AR inhibitor is ofFormula (I):

-   -   or a pharmaceutically acceptable salt or solvate thereof,        wherein:    -   R¹ represents 5- or 6-membered heteroaryl or 5- or 6-membered        aryl, wherein heteroaryl or aryl groups are optionally        substituted by one or more substituent selected from C1-C6 alkyl        (preferably methyl) and halo (preferably fluoro or chloro);        preferably R¹ represents 5-membered heteroaryl; more preferably        R¹ represents furyl;    -   R² represents 6-membered aryl or 6-membered heteroaryl,        -   wherein heteroaryl or aryl groups are optionally substituted            by one or more substituent selected from halo, alkyl,            heterocyclyl, alkoxy, cycloalkyloxy, heterocyclyloxy,            carbonyl, alkylcarbonyl, aminocarbonyl, hydroxycarbonyl,            heterocyclylcarbonyl, alkylsulfoxide, alkylsulfonyl,            aminosulfonyl, heterocyclylsulfonyl, alkylsulfonimidoyl,            carbonylamino, sulfonylamino and alkylsulfonealkyl;            -   said substituents being optionally substituted by one or                more substituent selected from oxo, halo, hydroxy,                cyano, alkyl, alkenyl, aldehyde, heterocyclylalkyl,                hydroxyalkyl, dihydroxyalkyl, hydroxyalkylaminoalkyl,                aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl,                (heterocyclyl)(alkyl)aminoalkyl, heterocyclyl,                heteroaryl, alkylheteroaryl, alkyne, alkoxy, amino,                dialkylamino, aminoalkylcarbonylamino,                aminocarbonylalkylamino,                (aminocarbonylalkyl)(alkyl)amino, alkenylcarbonylamino,                hydroxycarbonyl, alkyloxycarbonyl, aminocarbonyl,                aminoalkylaminocarbonyl, alkylaminoalkylaminocarbonyl,                dialkylaminoalkylaminocarbonyl,                heterocyclylalkylaminocarbonyl,                (alkylaminoalkyl)(alkyl)aminocarbonyl,                alkylaminoalkylcarbonyl, dialkylaminoalkylcarbonyl,                heterocyclylcarbonyl, alkenylcarbonyl, alkynylcarbonyl,                alkylsulfoxide, alkylsulfoxidealkyl, alkylsulfonyl and                alkylsulfonealkyl;        -   or the heteroaryl or aryl groups are optionally substituted            with two substituents that form together with the atoms to            which they are attached a 5- or 6-membered aryl ring, a 5-            or 6-membered heteroaryl ring, a 5- or 6-membered cycloalkyl            ring or a 5- or 6-membered heterocyclyl ring; optionally            substituted by one or more substituent selected from oxo,            halo, hydroxy, cyano, alkyl, alkenyl, aldehyde,            heterocyclylalkyl, hydroxyalkyl, dihydroxyalkyl,            hydroxyalkylaminoalkyl, aminoalkyl, alkylaminoalkyl,            dialkylaminoalkyl, (heterocyclyl)(alkyl)aminoalkyl,            heterocyclyl, heteroaryl, alkylheteroaryl, alkyne, alkoxy,            amino, dialkylamino, aminoalkylcarbonylamino,            aminocarbonylalkylamino, (aminocarbonylalkyl)(alkyl)amino,            alkenylcarbonylamino, hydroxycarbonyl, alkyloxycarbonyl,            aminocarbonyl, aminoalkylaminocarbonyl,            alkylaminoalkylaminocarbonyl,            dialkylaminoalkylaminocarbonyl,            heterocyclylalkylaminocarbonyl,            (alkylaminoalkyl)(alkyl)aminocarbonyl,            alkylaminoalkylcarbonyl, dialkylaminoalkylcarbonyl,            heterocyclylcarbonyl, alkenylcarbonyl, alkynylcarbonyl,            alkylsulfoxide, alkylsulfoxidealkyl, alkylsulfonyl and            alkylsulfonealkyl.

In one embodiment, preferred compounds of Formula (I) are of Formula(Ia):

-   -   or a pharmaceutically acceptable salt or solvate thereof,        wherein:    -   R¹ represents 5- or 6-membered heteroaryl or 5- or 6-membered        aryl, wherein heteroaryl or aryl groups are optionally        substituted by one or more substituent selected from C1-C6 alkyl        (preferably methyl) and halo (preferably fluoro or chloro);        preferably R¹ represents 5-membered heteroaryl; more preferably        R¹ represents furyl;    -   X¹ and X² represent each independently C or N;    -   R^(1′) is absent when X¹ is N; or when X¹ is C, R^(1′)        represents H, halo, alkyl, heterocyclyl, alkoxy, cycloalkyloxy,        heterocyclyloxy, carbonyl, alkylcarbonyl, aminocarbonyl,        hydroxycarbonyl, heterocyclylcarbonyl, alkylsulfoxide,        alkylsulfonyl, aminosulfonyl, heterocyclylsulfonyl,        alkylsulfonimidoyl, carbonylamino, sulfonylamino or        alkylsulfonealkyl;        -   said substituents being optionally substituted by one or            more substituent selected from oxo, halo, hydroxy, cyano,            alkyl, alkenyl, aldehyde, heterocyclylalkyl, hydroxyalkyl,            dihydroxyalkyl, hydroxyalkylaminoalkyl, aminoalkyl,            alkylaminoalkyl, dialkylaminoalkyl,            (heterocyclyl)(alkyl)aminoalkyl, heterocyclyl, heteroaryl,            alkylheteroaryl, alkyne, alkoxy, amino, dialkylamino,            aminoalkylcarbonylamino, aminocarbonylalkylamino,            (aminocarbonylalkyl)(alkyl)amino, alkenylcarbonylamino,            hydroxycarbonyl, alkyloxycarbonyl, aminocarbonyl,            aminoalkylaminocarbonyl, alkylaminoalkylaminocarbonyl,            dialkylaminoalkylaminocarbonyl,            heterocyclylalkylaminocarbonyl,            (alkylaminoalkyl)(alkyl)aminocarbonyl,            alkylaminoalkylcarbonyl, dialkylaminoalkylcarbonyl,            heterocyclylcarbonyl, alkenylcarbonyl, alkynylcarbonyl,            alkylsulfoxide, alkylsulfoxidealkyl, alkylsulfonyl and            alkylsulfonealkyl;    -   R^(2′) represents H, halo, alkyl, heterocyclyl, alkoxy,        cycloalkyloxy, heterocyclyloxy, carbonyl, alkylcarbonyl,        aminocarbonyl, hydroxycarbonyl, heterocyclylcarbonyl,        alkylsulfoxide, alkylsulfonyl, aminosulfonyl,        heterocyclylsulfonyl, alkylsulfonimidoyl, carbonylamino,        sulfonylamino, or alkylsulfonealkyl;        -   said substituents being optionally substituted by one or            more substituent selected from oxo, halo, hydroxy, cyano,            alkyl, alkenyl, aldehyde, heterocyclylalkyl, hydroxyalkyl,            dihydroxyalkyl, hydroxyalkylaminoalkyl, aminoalkyl,            alkylaminoalkyl, dialkylaminoalkyl,            (heterocyclyl)(alkyl)aminoalkyl, heterocyclyl, heteroaryl,            alkylheteroaryl, alkyne, alkoxy, amino, dialkylamino,            aminoalkylcarbonylamino, aminocarbonylalkylamino,            (aminocarbonylalkyl)(alkyl)amino, alkenylcarbonylamino,            hydroxycarbonyl, alkyloxycarbonyl, aminocarbonyl,            aminoalkylaminocarbonyl, alkylaminoalkylaminocarbonyl,            dialkylaminoalkylaminocarbonyl,            heterocyclylalkylaminocarbonyl,            (alkylaminoalkyl)(alkyl)aminocarbonyl,            alkylaminoalkylcarbonyl, dialkylaminoalkylcarbonyl,            heterocyclylcarbonyl, alkenylcarbonyl, alkynylcarbonyl,            alkylsulfoxide, alkylsulfoxidealkyl, alkylsulfonyl and            alkylsulfonealkyl;    -   or R^(1′) and R^(2′) form together with the atoms to which they        are attached a 5- or 6-membered aryl ring, a 5- or 6-membered        heteroaryl ring, a 5- or 6-membered cycloalkyl ring or a 5- or        6-membered heterocyclyl ring; optionally substituted by one or        more substituent selected from oxo, halo, hydroxy, cyano, alkyl,        alkenyl, aldehyde, heterocyclylalkyl, hydroxyalkyl,        dihydroxyalkyl, hydroxyalkylaminoalkyl, aminoalkyl,        alkylaminoalkyl, dialkylaminoalkyl,        (heterocyclyl)(alkyl)aminoalkyl, heterocyclyl, heteroaryl,        alkylheteroaryl, alkyne, alkoxy, amino, dialkylamino,        aminoalkylcarbonylamino, aminocarbonylalkylamino,        (aminocarbonylalkyl)(alkyl)amino, alkenylcarbonylamino,        hydroxycarbonyl, alkyloxycarbonyl, aminocarbonyl,        aminoalkylaminocarbonyl, alkylaminoalkylaminocarbonyl,        dialkylaminoalkylaminocarbonyl, heterocyclylalkylaminocarbonyl,        (alkylaminoalkyl)(alkyl)aminocarbonyl, alkylaminoalkylcarbonyl,        dialkylaminoalkylcarbonyl, heterocyclylcarbonyl,        alkenylcarbonyl, alkynylcarbonyl, alkylsulfoxide,        alkylsulfoxidealkyl, alkylsulfonyl and alkylsulfonealkyl;    -   R^(3′) is absent when X² is N; or when X² is C, R^(3′)        represents H or halo, preferably H or F;    -   R^(4′) represents H or halo, preferably H or F; and    -   R^(5′) represents H or halo, preferably H or F.

In one specific embodiment of the invention, R¹ represents 5- or6-membered heteroaryl or 5- or 6-membered aryl, wherein heteroaryl oraryl groups are optionally substituted by one or more substituentselected from C1-C6 alkyl (preferably methyl) and halo (preferablyfluoro or chloro). In a preferred embodiment, R¹ represents 5-memberedheteroaryl; more preferably, R¹ represents furyl.

In one specific embodiment of the invention, X¹ and X² represent eachindependently C or N. In another specific embodiment, X¹ and X² bothrepresent C.

In one specific embodiment of the invention, R^(1′) is absent when X¹ isN.

In another specific embodiment, when X¹ is C, R^(1′) represents H, halo,alkyl, heterocyclyl, alkoxy, cycloalkyloxy, heterocyclyloxy, carbonyl,alkylcarbonyl, aminocarbonyl, hydroxycarbonyl, heterocyclylcarbonyl,alkylsulfoxide, alkylsulfonyl, aminosulfonyl, heterocyclylsulfonyl,alkylsulfonimidoyl, carbonylamino, sulfonylamino or alkylsulfonealkyl;said substituents being optionally substituted by one or moresubstituent selected from oxo, halo, hydroxy, cyano, alkyl, alkenyl,aldehyde, heterocyclylalkyl, hydroxyalkyl, dihydroxyalkyl,hydroxyalkylaminoalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl,(heterocyclyl)(alkyl)aminoalkyl, heterocyclyl, heteroaryl,alkylheteroaryl, alkyne, alkoxy, amino, dialkylamino,aminoalkylcarbonylamino, aminocarbonylalkylamino,(aminocarbonylalkyl)(alkyl)amino, alkenylcarbonylamino, hydroxycarbonyl,alkyloxycarbonyl, aminocarbonyl, aminoalkylaminocarbonyl,alkylaminoalkylaminocarbonyl, dialkylaminoalkylaminocarbonyl,heterocyclylalkylaminocarbonyl, (alkylaminoalkyl)(alkyl)aminocarbonyl,alkylaminoalkylcarbonyl, dialkylaminoalkylcarbonyl,heterocyclylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, alkylsulfoxide,alkylsulfoxidealkyl, alkylsulfonyl and alkylsulfonealkyl.

In a preferred embodiment, R^(1′) substituents are optionallysubstituted by one or more substituent selected from halo, hydroxy,alkyl, heterocyclylalkyl, hydroxyalkyl, hydroxyalkylaminoalkyl,aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl,(heterocyclyl)(alkyl)aminoalkyl, heterocyclyl, heteroaryl,alkylheteroaryl, alkoxy, amino, dialkylamino, aminoalkylcarbonylamino,aminocarbonylalkylamino, heterocyclylalkylaminocarbonyl,(aminocarbonylalkyl)(alkyl)amino, hydroxycarbonyl, aminocarbonyl,aminoalkylaminocarbonyl, alkylaminoalkylaminocarbonyl,dialkylaminoalkylaminocarbonyl, (alkylaminoalkyl)(alkyl)aminocarbonyl,heterocyclylcarbonyl, alkylsulfoxide and alkylsulfonealkyl.

In one specific embodiment of the invention, R^(2′) represents H, halo,alkyl, heterocyclyl, alkoxy, cycloalkyloxy, heterocyclyloxy, carbonyl,alkylcarbonyl, aminocarbonyl, hydroxycarbonyl, heterocyclylcarbonyl,alkylsulfoxide, alkylsulfonyl, aminosulfonyl, heterocyclylsulfonyl,alkylsulfonimidoyl, carbonylamino, sulfonylamino, or alkylsulfonealkyl;said substituents being optionally substituted by one or moresubstituent selected from oxo, halo, hydroxy, cyano, alkyl, alkenyl,aldehyde, heterocyclylalkyl, hydroxyalkyl, dihydroxyalkyl,hydroxyalkylaminoalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl,(heterocyclyl)(alkyl)aminoalkyl, heterocyclyl, heteroaryl,alkylheteroaryl, alkyne, alkoxy, amino, dialkylamino,aminoalkylcarbonylamino, aminocarbonylalkylamino,(aminocarbonylalkyl)(alkyl)amino, alkenylcarbonylamino, hydroxycarbonyl,alkyloxycarbonyl, aminocarbonyl, aminoalkylaminocarbonyl,alkylaminoalkylaminocarbonyl, dialkylaminoalkylaminocarbonyl,heterocyclylalkylaminocarbonyl, (alkylaminoalkyl)(alkyl)aminocarbonyl,alkylaminoalkylcarbonyl, dialkylaminoalkylcarbonyl,heterocyclylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, alkylsulfoxide,alkylsulfoxidealkyl, alkylsulfonyl and alkylsulfonealkyl.

In a preferred embodiment, R^(2′) substituents are optionallysubstituted by one or more substituent selected from oxo, halo, hydroxy,cyano, alkyl, heterocyclylalkyl, dihydroxyalkyl, dialkylaminoalkyl,heteroaryl, alkylheteroaryl, hydroxycarbonyl, alkyloxycarbonyl,aminocarbonyl, heterocyclylalkylaminocarbonyl, alkylaminoalkylcarbonyl,dialkylaminoalkylcarbonyl, alkylsulfoxide, alkylsulfonealkyl.

In another specific embodiment of the invention, R^(1′) and R^(2′) formtogether with the atoms to which they are attached a 5- or 6-memberedaryl ring, a 5- or 6-membered heteroaryl ring, a 5- or 6-memberedcycloalkyl ring or a 5- or 6-membered heterocyclyl ring; optionallysubstituted by one or more substituent selected from oxo, halo, hydroxy,cyano, alkyl, alkenyl, aldehyde, heterocyclylalkyl, hydroxyalkyl,dihydroxyalkyl, hydroxyalkylaminoalkyl, aminoalkyl, alkylaminoalkyl,dialkylaminoalkyl, (heterocyclyl)(alkyl)aminoalkyl, heterocyclyl,heteroaryl, alkylheteroaryl, alkyne, alkoxy, amino, dialkylamino,aminoalkylcarbonylamino, aminocarbonylalkylamino,(aminocarbonylalkyl)(alkyl)amino, alkenylcarbonylamino, hydroxycarbonyl,alkyloxycarbonyl, aminocarbonyl, aminoalkylaminocarbonyl,alkylaminoalkylaminocarbonyl, dialkylaminoalkylaminocarbonyl,heterocyclylalkylaminocarbonyl, (alkylaminoalkyl)(alkyl)aminocarbonyl,alkylaminoalkylcarbonyl, dialkylaminoalkylcarbonyl,heterocyclylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, alkylsulfoxide,alkylsulfoxidealkyl, alkylsulfonyl and alkylsulfonealkyl.

In one specific embodiment of the invention, R^(3′) is absent when X² isN. In another specific embodiment of the invention, when X² is C, R^(3′)represents H or halo. In a preferred embodiment, when X² is C, R^(3′)represents H or F.

In one specific embodiment of the invention, R^(4′) represents H orhalo. In a preferred embodiment, R^(4′) represents H or F.

In one specific embodiment of the invention, R^(5′) represents H orhalo. In a preferred embodiment, R^(1′) represents H or F.

In one embodiment, preferred compounds of Formula (Ia) are those ofFormula (Ia-1):

-   -   or a pharmaceutically acceptable salt or solvate thereof,        wherein R¹, R^(1′), R^(2′), R^(3′), R^(4′) and R^(5′) are as        defined in Formula (Ia).

In one embodiment, preferred compounds of Formula (Ia-1) are those ofFormula (Ia-1a):

-   -   or a pharmaceutically acceptable salt or solvate thereof,        wherein:    -   R¹ and R^(3′) are as defined in Formula (Ia); and    -   R^(1″) represents an alkyl or heterocyclyl group substituted by        one or more group selected from oxo, halo, hydroxy, cyano,        alkyl, alkenyl, aldehyde, heterocyclylalkyl, hydroxyalkyl,        dihydroxyalkyl, hydroxyalkylaminoalkyl, aminoalkyl,        alkylaminoalkyl, dialkylaminoalkyl,        (heterocyclyl)(alkyl)aminoalkyl, heterocyclyl, heteroaryl,        alkylheteroaryl, alkyne, alkoxy, amino, dialkylamino,        aminoalkylcarbonylamino, aminocarbonylalkylamino,        (aminocarbonylalkyl)(alkyl)amino, alkenylcarbonylamino,        hydroxycarbonyl, alkyloxycarbonyl, aminocarbonyl,        aminoalkylaminocarbonyl, alkylaminoalkylaminocarbonyl,        dialkylaminoalkylaminocarbonyl, heterocyclylalkylaminocarbonyl,        (alkylaminoalkyl)(alkyl)aminocarbonyl, alkylaminoalkylcarbonyl,        dialkylaminoalkylcarbonyl, heterocyclylcarbonyl,        alkenylcarbonyl, alkynylcarbonyl, alkylsulfoxide,        alkylsulfoxidealkyl, alkylsulfonyl and alkylsulfonealkyl.

In one specific embodiment of the invention, R^(1″) represents an alkylor heterocyclyl group substituted by one or more group selected fromoxo, halo, hydroxy, cyano, alkyl, alkenyl, aldehyde, heterocyclylalkyl,hydroxyalkyl, dihydroxyalkyl, hydroxyalkylaminoalkyl, aminoalkyl,alkylaminoalkyl, dialkylaminoalkyl, (heterocyclyl)(alkyl)aminoalkyl,heterocyclyl, heteroaryl, alkylheteroaryl, alkyne, alkoxy, amino,dialkylamino, aminoalkylcarbonylamino, aminocarbonylalkylamino,(aminocarbonylalkyl)(alkyl)amino, alkenylcarbonylamino, hydroxycarbonyl,alkyloxycarbonyl, aminocarbonyl, aminoalkylaminocarbonyl,alkylaminoalkylaminocarbonyl, dialkylaminoalkylaminocarbonyl,heterocyclylalkylaminocarbonyl, (alkylaminoalkyl)(alkyl)aminocarbonyl,alkylaminoalkylcarbonyl, dialkylaminoalkylcarbonyl,heterocyclylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, alkylsulfoxide,alkylsulfoxidealkyl, alkylsulfonyl and alkylsulfonealkyl.

In a preferred embodiment, R^(1″) represents an alkyl or heterocyclylgroup substituted by one or more group selected from hydroxy,heterocyclyl, heteroaryl, alkylheteroaryl, alkyne, alkoxy, amino,dialkylamino, aminoalkylcarbonylamino, aminocarbonylalkylamino,(aminocarbonylalkyl)(alkyl)amino, hydroxycarbonyl, aminocarbonyl,aminoalkylaminocarbonyl, alkylaminoalkylaminocarbonyl,dialkylaminoalkylaminocarbonyl, (alkylaminoalkyl)(alkyl)aminocarbonyl,heterocyclylcarbonyl, alkylsulfoxide, alkylsulfonealkyl.

In one embodiment, preferred compounds of Formula (Ia-1) are those ofFormula (Ia-1b):

-   -   or a pharmaceutically acceptable salt or solvate thereof,        wherein:    -   R¹ and R^(3′) are as defined in Formula (Ia);    -   R^(1′) represents H or halo, preferably H or F; and    -   R^(2″) represents an alkyl or heterocyclyl group substituted by        one or more group selected from oxo, halo, hydroxy, cyano,        alkyl, alkenyl, aldehyde, heterocyclylalkyl, hydroxyalkyl,        dihydroxyalkyl, hydroxyalkylaminoalkyl, aminoalkyl,        alkylaminoalkyl, dialkylaminoalkyl,        (heterocyclyl)(alkyl)aminoalkyl, heterocyclyl, heteroaryl,        alkylheteroaryl, alkyne, alkoxy, amino, dialkylamino,        aminoalkylcarbonylamino, aminocarbonylalkylamino,        (aminocarbonylalkyl)(alkyl)amino, alkenylcarbonylamino,        hydroxycarbonyl, alkyloxycarbonyl, aminocarbonyl,        aminoalkylaminocarbonyl, alkylaminoalkylaminocarbonyl,        dialkylaminoalkylaminocarbonyl, heterocyclylalkylaminocarbonyl,        (alkylaminoalkyl)(alkyl)aminocarbonyl, alkylaminoalkylcarbonyl,        dialkylaminoalkylcarbonyl, heterocyclylcarbonyl,        alkenylcarbonyl, alkynylcarbonyl, alkylsulfoxide,        alkylsulfoxidealkyl, alkylsulfonyl and alkylsulfonealkyl.

In one specific embodiment of the invention, R^(1′) represents H orhalo. In a preferred embodiment, R^(1′) represents H or F.

In one specific embodiment of the invention, R^(2″) represents an alkylor heterocyclyl group substituted by one or more group selected fromoxo, halo, hydroxy, cyano, alkyl, alkenyl, aldehyde, heterocyclylalkyl,hydroxyalkyl, dihydroxyalkyl, hydroxyalkylaminoalkyl, aminoalkyl,alkylaminoalkyl, dialkylaminoalkyl, (heterocyclyl)(alkyl)aminoalkyl,heterocyclyl, heteroaryl, alkylheteroaryl, alkyne, alkoxy, amino,dialkylamino, aminoalkylcarbonylamino, aminocarbonylalkylamino,(aminocarbonylalkyl)(alkyl)amino, alkenylcarbonylamino, hydroxycarbonyl,alkyloxycarbonyl, aminocarbonyl, aminoalkylaminocarbonyl,alkylaminoalkylaminocarbonyl, dialkylaminoalkylaminocarbonyl,heterocyclylalkylaminocarbonyl, (alkylaminoalkyl)(alkyl)aminocarbonyl,alkylaminoalkylcarbonyl, dialkylaminoalkylcarbonyl,heterocyclylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, alkylsulfoxide,alkylsulfoxidealkyl, alkylsulfonyl and alkylsulfonealkyl.

In a preferred embodiment, R^(2″) represents an alkyl or heterocyclylgroup substituted by one or more group selected from hydroxy, cyano,heteroaryl, alkylheteroaryl, alkyne, hydroxycarbonyl, alkyloxycarbonyl,aminocarbonyl, alkylaminoalkylcarbonyl, dialkylaminoalkylcarbonyl,alkylsulfoxide, alkylsulfonealkyl.

In one embodiment, preferred compounds of Formula (Ia-1) are those ofFormula (Ia-1c) or (Ia-1d):

-   -   or a pharmaceutically acceptable salt or solvate thereof,        wherein:    -   R¹ and R^(3′) are as defined in Formula (Ia);    -   R^(1′) represents H or halo, preferably H or F;    -   R^(2′) represents H or halo, preferably H or F;    -   R^(1i) and R^(1ii) represent each independently hydrogen,        hydroxy, alkyl, alkenyl, heterocyclylalkyl, hydroxyalkyl,        dihydroxyalkyl, hydroxyalkylaminoalkyl, aminoalkyl,        alkylaminoalkyl, dialkylaminoalkyl,        (heterocyclyl)(alkyl)aminoalkyl, heterocyclyl, heteroaryl,        alkylheteroaryl, alkynealkyl, alkoxy, amino, dialkylamino,        aminoalkylcarbonylamino, aminocarbonylalkylamino,        (aminocarbonylalkyl)(alkyl)amino, alkenylcarbonylamino,        hydroxycarbonyl, alkyloxycarbonyl, aminocarbonyl,        aminoalkylaminocarbonyl, alkylaminoalkylaminocarbonyl,        dialkylaminoalkylaminocarbonyl, heterocyclylalkylaminocarbonyl,        (alkylaminoalkyl)(alkyl)aminocarbonyl, alkylaminoalkylcarbonyl,        dialkylaminoalkylcarbonyl, heterocyclylcarbonyl,        alkenylcarbonyl, alkynylcarbonyl, alkylsulfoxidealkyl or        alkylsulfonealkyl; and    -   R^(2i) and R^(2ii) represent each independently hydrogen,        hydroxy, alkyl, alkenyl, heterocyclylalkyl, hydroxyalkyl,        dihydroxyalkyl, hydroxyalkylaminoalkyl, aminoalkyl,        alkylaminoalkyl, dialkylaminoalkyl,        (heterocyclyl)(alkyl)aminoalkyl, heterocyclyl, heteroaryl,        alkylheteroaryl, alkynealkyl, alkoxy, amino, dialkylamino,        aminoalkylcarbonylamino, aminocarbonylalkylamino,        (aminocarbonylalkyl)(alkyl)amino, alkenylcarbonylamino,        hydroxycarbonyl, alkyloxycarbonyl, aminocarbonyl,        aminoalkylaminocarbonyl, alkylaminoalkylaminocarbonyl,        dialkylaminoalkylaminocarbonyl, heterocyclylalkylaminocarbonyl,        (alkylaminoalkyl)(alkyl)aminocarbonyl, alkylaminoalkylcarbonyl,        dialkylaminoalkylcarbonyl, heterocyclylcarbonyl,        alkenylcarbonyl, alkynylcarbonyl, alkylsulfoxidealkyl or        alkylsulfonealkyl.

In one specific embodiment of the invention, R^(1′) represents H orhalo. In a preferred embodiment, R^(1′) represents H or F.

In one specific embodiment of the invention, R^(2′) represents H orhalo. In a preferred embodiment, R^(2′) represents H or F.

In one specific embodiment of the invention, R^(1i) and R^(1ii)represent each independently hydrogen, hydroxy, alkyl, alkenyl,heterocyclylalkyl, hydroxyalkyl, dihydroxyalkyl, hydroxyalkylaminoalkyl,aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl,(heterocyclyl)(alkyl)aminoalkyl, heterocyclyl, heteroaryl,alkylheteroaryl, alkynealkyl, alkoxy, amino, dialkylamino,aminoalkylcarbonylamino, aminocarbonylalkylamino,(aminocarbonylalkyl)(alkyl)amino, alkenylcarbonylamino, hydroxycarbonyl,alkyloxycarbonyl, aminocarbonyl, aminoalkylaminocarbonyl,alkylaminoalkylaminocarbonyl, dialkylaminoalkylaminocarbonyl,heterocyclylalkylaminocarbonyl, (alkylaminoalkyl)(alkyl)aminocarbonyl,alkylaminoalkylcarbonyl, dialkylaminoalkylcarbonyl,heterocyclylcarbonyl, alkenylcarbonyl, alkynylcarbonyl,alkylsulfoxidealkyl or alkylsulfonealkyl.

In a preferred embodiment, R^(1i) and R^(1ii) represent eachindependently hydrogen, alkyl, heterocyclylalkyl, hydroxyalkyl,hydroxyalkylaminoalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl,(heterocyclyl)(alkyl)aminoalkyl or heterocyclylalkylaminocarbonyl.

In one specific embodiment of the invention, R^(2i) and R^(2ii)represent each independently hydrogen, hydroxy, alkyl, alkenyl,heterocyclylalkyl, hydroxyalkyl, dihydroxyalkyl, hydroxyalkylaminoalkyl,aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl,(heterocyclyl)(alkyl)aminoalkyl, heterocyclyl, heteroaryl,alkylheteroaryl, alkynealkyl, alkoxy, amino, dialkylamino,aminoalkylcarbonylamino, aminocarbonylalkylamino,(aminocarbonylalkyl)(alkyl)amino, alkenylcarbonylamino, hydroxycarbonyl,alkyloxycarbonyl, aminocarbonyl, aminoalkylaminocarbonyl,alkylaminoalkylaminocarbonyl, dialkylaminoalkylaminocarbonyl,heterocyclylalkylaminocarbonyl, (alkylaminoalkyl)(alkyl)aminocarbonyl,alkylaminoalkylcarbonyl, dialkylaminoalkylcarbonyl,heterocyclylcarbonyl, alkenylcarbonyl, alkynylcarbonyl,alkylsulfoxidealkyl or alkylsulfonealkyl.

In a preferred embodiment, R^(2i) and R^(2ii) represent eachindependently hydrogen, alkyl, heterocyclylalkyl, dihydroxyalkyl,dialkylaminoalkyl or heterocyclylalkylaminocarbonyl. In a preferredembodiment, R^(2i) and R^(2ii) represent each independently hydrogen,alkyl or dialkylaminoalkyl.

In one embodiment, preferred compounds of Formula (Ia) are those ofFormulae (Ia-2) or (Ia-3):

-   -   or a pharmaceutically acceptable salt or solvate thereof,        wherein R¹, R^(2′), R^(3′), R^(4′) and R^(5′) are as defined in        Formula (Ia).

Particularly preferred compounds of Formula (I) of the invention arethose listed in Table 1 hereafter.

TABLE 1 Cpd no Structure Chemical name MW   1

3-(2-(4-(4-((1H-1,2,3- triazolo-4yl)methoxy- 2fluorophenyl)piperazine-1-yl)ethyl)-5-amino-(8-(furan- 2-yl)thiazolo[5,4- e][1,2,4]triazolo[1,5-c]pyrimidine-2(3H)-one 577.60   2

5-((4-(4-(2-(5-amino-8- (furan-2-yl)-2-oxothiazolo[5,4-e][1,2,4]triazolo[1,5- c]pyrimidin-3(2H)-yl)ethyl)piperazin-1-yl)-3- fluorophenoxy)methyl)-1,3,4-oxadiazol-2(3H)-one 594.58   3

5-amino-3-(2-(4-(3- fluoropyridin-4- yl)piperazin-1-yl)ethyl)-8-(furan-2-yl)thiazolo[5,4- e][1,2,4]triazolo[1,5- c]pyrimidin-2(3H)-one481.51   4

2-(5-(4-(2-(5-amino-8- (furan-2-yl)-2- oxothiazolo[5,4-e][1,2,4]triazolo[1,5-c] pyrimidin-3(2H)- yl)ethyl)piperazin-1-yl)-2,4-difluorophenoxy)acetamide 571.56   5

(S)-5-amino-3-(2-(4-(2- fluoro-4-(2- (methylsulfinyl)ethoxy)phen-yl)piperazin-1-yl)ethyl)-8- (furan-2-yl)thiazolo[5,4-e][1,2,4]triazolo[1,5- c]pyrimidin-2(3H)-one 586.66   6

(R)-5-amino-3-(2-(4-(2- fluoro-4-(2- (methylsulfinyl)ethoxy)phen-yl)-piperazin-1-yl)ethyl)-8- (furan-2-yl)thiazolo[5,4-e][1,2,4]triazolo[1,5- c]pyrimidin-2(3H)-one 586.66   7

(R,S)-5-amino-3-(2-(4-(2,4- difluoro-5-(2- (methylsulfinyl)ethoxy)phen-yl)piperazin-1-yl)ethyl)-8- (furan-2-yl)thiazolo[5,4-e][1,2,4]triazolo[1,5- c]pyrimidin-2(3H)-one 604.65   8a

(+)-5-amino-3-(2-(4-(2,4- difluoro-5-(2- (methylsulfinyl)ethoxy)phen-yl)piperazin-1-yl)ethyl)-8- (furan-2-yl)thiazolo[5,4-e][1,2,4]triazolo[1,5- c]pyrimidin-2(3H)-one 604.65   8b

(−)-5-amino-3-(2-(4-(2,4- difluoro-5-(2- (methylsulfinyl)ethoxy)phen-yl)piperazin-1-yl)ethyl)-8- (furan-2-yl)thiazolo[5,4-e][1,2,4]triazolo[1,5- c]pyrimidin-2(3H)-one 604.65   9

5-amino-8-(furan-2-yl)-3- (2-(4-(4-(2-hydroxyethoxy) phenyl)piperazin-1-yl)ethyl)thiazolo[5,4- e][1,2,4]triazolo[1,5- c]pyrimidin-2(3H)-one522.58  10

2-(4-(4-(2-(5-amino-8- (furan-2-yl)-2-oxothiazolo[5,4-e][1,2,4]triazolo[1,5- c]pyrimidin-3(2H)- yl)ethyl)piperazin-1-yl)phenoxy)acetic acid 536.56  11

2-(4-(4-(2-(5-amino-8- (furan-2-yl)-2-oxothiazolo[5,4-e][1,2,4]triazolo[1,5- c]pyrimidin-3(2H)- yl)ethyl)piperazin-1-yl)phenoxy)acetamide 535.58  12

5-amino-3-(2-(4-(4-(2,3- dihydroxypropoxy)phenyl)piperazin-1-yl)ethyl)-8- (furan-2-yl)thiazolo[5,4-e][1,2,4]triazolo[1,5- c]pyrimidin-2(3H)-one 552.61  13

5-amino-3-(2-(4-(4-(2- aminoethoxy)phenyl)pipera-zin-1-yl)ethyl)-8-(furan-2- yl)thiazolo[5,4-e] [1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one 521.60 14

4-(4-(2-(5-amino-8-(furan- 2-yl)-2-oxothiazolo[5,4-e][1,2,4]triazolo[1,5- c]pyrimidin-3(2H)-yl) ethyl)piperazin-1-yl)benzamide 505.55  15

4-(4-(2-(5-amino-8-(furan- 2-yl)-2-oxothiazolo[5,4-e][1,2,4]triazolo[1,5- c]pyrimidin-3(2H)- yl)ethyl)piperazin-1-yl)-N-methylbenzamide 519.58  16

5-amino-8-(furan-2-yl)-3- (2-(4-(4-(2- morpholinoethoxy)phenyl)piperazin-1- yl)ethyl)thiazolo[5,4- e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one 591.68  17

5-amino-3-(2-(4-(4-(2- (dimethylamino)ethoxy)phen-yl)piperazin-1-yl)ethyl)-8- (furan-2-yl)thiazolo[5,4-e][1,2,4]triazolo[1,5- c]pyrimidin-2(3H)-one 549.65  18

4-(4-(2-(5-amino-8-(furan- 2-yl)-2-oxothiazolo[5,4-e][1,2,4]triazolo[1,5- c]pyrimidin-3(2H)- yl)ethyl)piperazin-1-yl)benzenesulfonamide 541.61  19

4-(4-(2-(5-amino-8-(furan- 2-yl)-2-oxothiazolo[5,4-e][1,2,4]triazolo[1,5-c] pyrimidin-3(2H)-yl)ethyl) piperazin-1-yl)-N-methylbenzenesulfonamide 555.63  20

5-amino-8-(furan-2-yl)-3- (2-(4-(4-(methylsulfonyl) phenyl)piperazin-1-yl)ethyl)thiazolo[5,4- e][1,2,4]triazolo[1,5- c]pyrimidin-2(3H)-one540.62  21

5-amino-8-(furan-2-yl)-3- (2-(4-(4-(methylsulfinyl) phenyl)piperazin-1-yl)ethyl)thiazolo[5,4- e][1,2,4]triazolo[1,5- c]pyrimidin-2(3H)-one524.62  22

3-(4-(2-(5-amino-8-(furan- 2-yl)-2-oxothiazolo[5,4-e][1,2,4]triazolo[1,5- c]pyrimidin-3(2H)- yl)ethyl)piperazin-1-yl)benzamide 505.55  23

5-amino-8-(furan-2-yl)-3- (2-(4-(3-(2-hydroxyethoxy) phenyl)piperazin-1-yl)ethyl)thiazolo[5,4- e][1,2,4]triazolo[1,5- c]pyrimidin-2(3H)-one522.58  24

5-amino-3-(2-(4-(2-fluoro- 4-(2-oxo-2-(piperazin-1-yl)ethoxy)phenyl)piperazin- 1-yl)ethyl)-8-(furan-2- yl)thiazolo[5,4-e][1,2,4]triazolo[1,5- c]pyrimidin-2(3H)-one 622.67  25

5-amino-3-(2-(4-(2-fluoro- 4-(piperidin-4-ylmethoxy) phenyl)piperazin-1-yl)ethyl)-8-(furan-2- yl)thiazolo[5,4- e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one 593.68  26

5-amino-3-(2-(4-(2-fluoro- 4-(piperazine-1-carbonyl) phenyl)piperazin-1-yl)ethyl)-8-(furan-2- yl)thiazolo[5,4- e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one 592.65  27

5-amino-3-(2-(4-(2-fluoro- 4-(2-(piperazin-1-yl)ethoxy)phenyl)piperazin- 1-yl)ethyl)-8-(furan-2- yl)thiazolo[5,4-e][1,2,4]triazolo[1,5- c]pyrimidin-2(3H)-one 608.69  28

5-amino-3-(2-(4-(2-fluoro- 4-(piperazin-1- ylsulfonyl)phenyl)piperazin-1-yl)ethyl)-8-(furan-2- yl)thiazolo[5,4- e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one 628.70  29

5-amino-3-(2-(4-(2-fluoro- 4-(methylsulfonyl)phenyl)piperazin-1-yl)ethyl)-8- (furan-2-yl)thiazolo[5,4-e][1,2,4]triazolo[1,5- c]pyrimidin-2(3H)-one 558.61  30

4-(4-(2-(5-amino-8-(furan- 2-yl)-2-oxothiazolo[5,4-e][1,2,4]triazolo[1,5- c]pyrimidin-3(2H)- yl)ethyl)piperazin-1-yl)-N-(2-aminoethyl)-3- fluorobenzamide 566.61  31

4-(4-(2-(5-amino-8-(furan- 2-yl)-2-oxothiazolo[5,4-e][1,2,4]triazolo[1,5- c]pyrimidin-3(2H)- yl)ethyl)piperazin-1-yl)-3-fluoro-N-(2- (methylamino)ethyl) benzamide 580.64  32

4-(4-(2-(5-amino-8-(furan- 2-yl)-2-oxothiazolo[5,4-e][1,2,4]triazolo[1,5- c]pyrimidin-3(2H)- yl)ethyl)piperazin-1-yl)-N-(2-(dimethylamino)ethyl)-3- fluorobenzamide 594.66  33

4-(4-(2-(5-amino-8-(furan- 2-yl)-2-oxothiazolo[5,4-e][1,2,4]triazolo[1,5- c]pyrimidin-3(2H)- yl)ethyl)piperazin-1-yl)-3-fluoro-N-(2- hydroxyethyl)benzamide 567.60  34

4-(4-(2-(5-amino-8-(furan- 2-yl)-2-oxothiazolo[5,4-e][1,2,4]triazolo[1,5- c]pyrimidin-3(2H)- yl)ethyl)piperazin-1-yl)-N-(2,3-dihydroxypropyl)-3- fluorobenzamide 597.62  35

2-(4-(4-(2-(5-amino-8- (furan-2-yl)-2- oxothiazolo[5,4-e][1,2,4]triazolo[1,5- c]pyrimidin-3(2H)- yl)ethyl)piperazin-1-yl)-3-fluorophenoxy)acetic acid 554.55  36

2-(4-(4-(2-(5-amino-8- (furan-2-yl)-2-oxothiazolo[5,4-e][1,2,4]triazolo[1,5- c]pyrimidin-3(2H)-yl)ethyl)piperazin-1-yl)-3,5- difluorophenoxy) acetic acid 572.54  37

2-(4-(4-(2-(5-amino-8- (furan-2-yl)-2- oxothiazolo[5,4-e][1,2,4]triazolo[1,5- c]pyrimidin-3(2H)- yl)ethyl)piperazin-1-yl)-3-fluorophenoxy)propanoic acid 568.58  38

(S)-2-(4-(4-(2-(5-amino-8- (furan-2-yl)-2-oxothiazolo[5,4-e][1,2,4]triazolo[1,5- c]pyrimidin-3(2H)-yl)ethyl)piperazin-1-yl)-3- fluorophenoxy)propanoic acid 568.58  39

2-(4-(4-(2-(5-amino-8- (furan-2-yl)-2- oxothiazolo[5,4-e][1,2,4]triazolo[1,5- c]pyrimidin-3(2H)- yl)ethyl)piperazin-1-yl)-3-fluorophenoxy)-2- methylpropanoic acid 582.61  40

3-(4-(4-(2-(5-amino-8- (furan-2-yl)-2- oxothiazolo[5,4-e][1,2,4]triazolo[1,5- c]pyrimidin-3(2H)- yl)ethyl)piperazin-1-yl)-3-fluorophenyl)propanoic acid 552.58  41

4-(4-(4-(2-(5-amino-8- (furan-2-yl)-2-oxothiazolo[5,4-e][1,2,4]triazolo[1,5- c]pyrimidin-3(2H)-yl)ethyl)piperazin-1-yl)-3- fluorophenoxy)butanoic acid 582.61  42

2-(3-(4-(2-(5-amino-8- (furan-2-yl)-2- oxothiazolo[5,4-e][1,2,4]triazolo[1,5- c]pyrimidin-3(2H)- yl)ethyl)piperazin-1-yl)-2,6-difluorophenoxy) acetic acid 572.54  43

2-(5-(4-(2-(5-amino-8- (furan-2-yl)-2- oxothiazolo[5,4-e][1,2,4]triazolo[1,5- c]pyrimidin-3(2H)- yl)ethyl)piperazin-1-yl)-2,4-difluorophenoxy) acetic acid 572.54  44

4-(4-(2-(5-amino-8-(furan- 2-yl)-2-oxothiazolo[5,4-e][1,2,4]triazolo[1,5- c]pyrimidin-3(2H)- yl)ethyl)piperazin-1-yl)-3-fluorobenzoic acid 524.53  45

2-((2-(4-(4-(2-(5-amino-8- (furan-2-yl)-2-oxothiazolo[5,4-e][1,2,4]triazolo[1,5- c]pyrimidin-3(2H)-yl)ethyl)piperazin-1-yl)-3- fluorophenoxy)ethyl) amino)acetamide 596.64 46

2-((2-(4-(4-(2-(5-amino-8- (furan-2-yl)-2-oxothiazolo[5,4-e][1,2,4]triazolo[1,5- c]pyrimidin-3(2H)-yl)ethyl)piperazin-1-yl)-3- fluorophenoxy)ethyl)(methyl) amino)acetamide610.66  47

5-amino-3-(2-(4-(2-fluoro- 4-(piperidin-4-yloxy) phenyl)piperazin-1-yl)ethyl)-8-(furan-2-yl) thiazolo[5,4-e][1,2,4] triazolo[1,5-c]pyrimidin-2(3H)-one 579.65  48

5-amino-3-(2-(4-(2-fluoro- 4-(pyrrolidin-3- yloxy)phenyl)piperazin-1-yl)ethyl)-8-(furan-2- yl)thiazolo[5,4- e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one 565.62  49

3-(2-(4-(4-((1H-1,2,4- triazol-3-yl)methoxy)-2-fluorophenyl)piperazin-1- yl)ethyl)-5-amino-8-(furan- 2-yl)thiazolo[5,4-e][1,2,4]triazolo[1,5- c]pyrimidin-2(3H)-one 577.59  50

2-(4-(4-(2-(5-amino-8- (furan-2-yl)-2-oxothiazolo[5,4-e][1,2,4]triazolo[1,5- c]pyrimidin-3(2H)-yl)ethyl)piperazin-1-yl)-3- fluorophenoxy)-N-(2- (methylamino)ethyl)acetamide 610.66  51

2-(4-(4-(2-(5-amino-8- (furan-2-yl)-2-oxothiazolo[5,4-e][1,2,4]triazolo[1,5- c]pyrimidin-3(2H)-yl)ethyl)piperazin-1-yl)-3- fluorophenoxy)-N-(2- (dimethylamino)ethyl)acetamide 624.69  52

2-(4-(4-(2-(5-amino-8- (furan-2-yl)-2-oxothiazolo[5,4-e][1,2,4]triazolo[1,5- c]pyrimidin-3(2H)-yl)ethyl)piperazin-1-yl)-3- fluorophenoxy)-N-(2- aminoethyl)acetamide596.64  53

(R)-2-(4-(4-(2-(5-amino-8- (furan-2-yl)-2-oxothiazolo[5,4-e][1,2,4]triazolo[1,5- c]pyrimidin-3(2H)-yl)ethyl)piperazin-1-yl)-3- fluorophenoxy)propanoic acid 568.58  54

2-(4-(4-(2-(5-amino-8- (furan-2-yl)-2-oxothiazolo[5,4-e][1,2,4]triazolo[1,5- c]pyrimidin-3(2H)-yl)ethyl)piperazin-1-yl)-3- fluorophenoxy)acetamide 553.57  55

4-(4-(2-(5-amino-8-(furan- 2-yl)-2-oxothiazolo[5,4-e][1,2,4]triazolo[1,5- c]pyrimidin-3(2H)- yl)ethyl)piperazin-1-yl)-3-fluoro-N-methyl-N-(2- (methylamino)ethyl) benzamide 594.66  56

4-(4-(2-(5-amino-8-(furan- 2-yl)-2-oxothiazolo[5,4-e][1,2,4]triazolo[1,5- c]pyrimidin-3(2H)- yl)ethyl)piperazin-1-yl)-N-(2-(dimethylamino)ethyl)-3- fluoro-N-methylbenzamide 608.69  57

(R)-4-(4-(2-(5-amino-8- (furan-2-yl)-2-oxothiazolo[5,4-e][1,2,4]triazolo[1,5- c]pyrimidin-3(2H)-yl)ethyl)piperazin-1-yl)-N-(1- (dimethylamino)propan-2-yl)-3-fluorobenzamide 608.69  58

2-(4-(4-(2-(5-amino-8- (furan-2-yl)-2-oxothiazolo[5,4-e][1,2,4]triazolo[1,5- c]pyrimidin-3(2H)-yl)ethyl)piperazin-1-yl)-3- fluorophenoxy)-N-methyl-N-(2-(methylamino)ethyl) acetamide 624.69  59

2-(5-(4-(2-(5-amino-8- (furan-2-yl)-2-oxothiazolo[5,4-e][1,2,4]triazolo[1,5- c]pyrimidin-3(2H)-yl)ethyl)piperazin-1-yl)-2,4- difluorophenoxy)-2- methylpropanoic acid600.60  60

(S)-2-(5-(4-(2-(5-amino-8- (furan-2-yl)-2-oxothiazolo[5,4-e][1,2,4]triazolo[1,5- c]pyrimidin-3(2H)-yl)ethyl)piperazin-1-yl)-2,4- difluorophenoxy) propanoic acid 586.57  61

(R)-2-(5-(4-(2-(5-amino-8- (furan-2-yl)-2-oxothiazolo[5,4-e][1,2,4]triazolo[1,5- c]pyrimidin-3(2H)-yl)ethyl)piperazin-1-yl)-2,4- difluorophenoxy) propanoic acid 586.57  62

2-(5-(4-(2-(5-amino-8- (furan-2-yl)-2- oxothiazolo[5,4-e][1,2,4]triazolo[1,5- c]pyrimidin-3(2H)- yl)ethyl)piperazin-1-yl)-2,4-difluorophenoxy)-N-(2- (methylamino)ethyl) acetamide 628.65  63

2-(5-(4-(2-(5-amino-8- (furan-2-yl)-2-oxothiazolo[5,4-e][1,2,4]triazolo[1,5- c]pyrimidin-3(2H)-yl)ethyl)piperazin-1-yl)-2,4- difluorophenoxy)-N-(2-(dimethylamino)ethyl) acetamide 642.68  64

5-(4-(2-(5-amino-8-(furan- 2-yl)-2-oxothiazolo[5,4-e][1,2,4]triazolo[1,5- c]pyrimidin-3(2H)- yl)ethyl)piperazin-1-yl)-N-(2-(dimethylamino)ethyl)- 2,4-difluoro-N- methylbenzamide 626.69  65

4-(5-(4-(2-(5-amino-8- (furan-2-yl)-2-oxothiazolo[5,4-e][1,2,4]triazolo[1,5- c]pyrimidin-3(2H)-yl)ethyl)piperazin-1-yl)-2,4- difluorophenoxy) butanoic acid 600.60  66

3-(2-(4-(5-((1H-tetrazol-5- yl)methoxy)-2,4- difluorophenyl)piperazin-1-yl)ethyl)-5-amino-8-(furan- 2-yl)thiazolo[5,4- e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one 596.58  67

5-amino-3-(2-(4-(2-fluoro- 4-((1-methyl-1H-1,2,4- triazol-3-yl)methoxy)phenyl)piperazin-1- yl)ethyl)-8-(furan-2- yl)thiazolo[5,4-e][1,2,4]triazolo[1,5- c]pyrimidin-2(3H)-one 591.62  68

5-amino-3-(2-(4-(2,4- difluoro-5-((1-methyl-1H- 1,2,4-triazol-3-yl)methoxy)phenyl)piperazin- 1-yl)ethyl)-8-(furan-2- yl)thiazolo[5,4-e][1,2,4]triazolo[1,5- c]pyrimidin-2(3H)-one 609.62  69

4-(4-(2-(5-amino-8-(furan- 2-yl)-2-oxothiazolo[5,4-e][1,2,4]triazolo[1,5- c]pyrimidin-3(2H)-yl) ethyl)piperazin-1-yl)-3-fluoro-N-(2-(methyl (oxetan-3-yl)amino)ethyl) benzamide 636.70  70

4-(4-(2-(5-amino-8-(furan- 2-yl)-2-oxothiazolo[5,4-e][1,2,4]triazolo[1,5- c]pyrimidin-3(2H)- yl)ethyl)piperazin-1-yl)-3-fluoro-N-(2-((2- hydroxyethyl)amino)ethyl) benzamide 610.67  71

2-amino-N-(2-(4-(4-(2-(5- amino-8-(furan-2-yl)-2- oxothiazolo[5,4-e][1,2,4]triazolo[1,5-c] pyrimidin-3(2H)-yl) ethyl)piperazin-1-yl)-3-fluorophenoxy)ethyl) acetamide 596.64  72

(S)-2-amino-N-(2-(4-(4-(2- (5-amino-8-(furan-2-yl)-2- oxothiazolo[5,4-e][1,2,4]triazolo[1,5- c]pyrimidin-3(2H)- yl)ethyl)piperazin-1-yl)-3-fluorophenoxy)ethyl)-3- methylbutanamide 638.72  73

ethyl 2-(5-(4-(2-(5-amino-8- (furan-2-yl)-2- oxothiazolo[5,4-e][1,2,4]triazolo[1,5-c] pyrimidin-3(2H)-yl) ethyl)piperazin-1-yl)-2,4-difluorophenoxy) acetate 600.60  74

2-(5-(4-(2-(5-amino-8- (furan-2-yl)-2- oxothiazolo[5,4-e][1,2,4]triazolo[1,5- c]pyrimidin-3(2H)- yl)ethyl)piperazin-1-yl)-2,4-difluorophenoxy) acetonitrile 553.54  75

5-amino-8-(furan-2-yl)-3- (2-(4-(pyridin-4-yl) piperazin-1-yl)ethyl)thiazolo[5,4- e][1,2,4]triazolo[1,5- c]pyrimidin-2(3H)-one463.52  76

5-amino-8-(furan-2-yl)-3- (2-(4-(pyrimidin-4- yl)piperazin-1-yl)ethyl)thiazolo[5,4- e][1,2,4]triazolo[1,5- c]pyrimidin-2(3H)-one464.50  77

5-amino-3-(2-(4-(2,4- difluoro-5-(2- (methylsulfonyl)ethoxy)phen-yl)piperazin-1-yl)ethyl)-8- (furan-2-yl)thiazolo[5,4-e][1,2,4]triazolo[1,5- c]pyrimidin-2(3H)-one 620.65  78

5-amino-3-(2-(4-(2-fluoro- 4-(2- (methylsulfonyl)ethoxy)phenyl)piperazin-1- yl)ethyl)-8- (furan-2-yl)thiazolo[5,4-e][1,2,4]triazolo[1,5- c]pyrimidin-2(3H)-one 602.66  79

5-amino-3-(2-(4-(6-fluoro- 2-oxoindolin-5- yl)piperazin-1-yl)ethyl)-8-(furan-2-yl)thiazolo[5,4- e][1,2,4]triazolo[1,5- c]pyrimidin-2(3H)-one535.55  80

5-amino-3-(2-(4-(2-fluoro- 4-(S- methylsulfonimidoyl)phenyl)piperazin-1-yl)ethyl)-8- (furan-2-yl)thiazolo[5,4-e][1,2,4]triazolo[1,5- c]pyrimidin-2(3H)-one 557.62  81

5-(4-(2-(5-amino-8-(furan- 2-yl)-2-oxothiazolo[5,4-e][1,2,4]triazolo[1,5- c]pyrimidin-3(2H)- yl)ethyl)piperazin-1-yl)-N-(2-(dimethylamino)ethyl)- 2,4-difluorobenzamide 612.65  82

5-amino-3-(2-(4-(5-fluoro- 2-methylpyridin-4-yl)piperazin-1-yl)ethyl)-8- (furan-2-yl)thiazolo[5,4-e][1,2,4]triazolo[1,5- c]pyrimidin-2(3H)-one 495.53  83

5-amino-3-(2-(4-(2-fluoro- 4-(((3R,4R)-4- hydroxytetrahydrofuran-3-yl)oxy)phenyl)piperazin-1- yl)ethyl)-8-(furan-2- yl)thiazolo[5,4-e][1,2,4]triazolo[1,5- c]pyrimidin-2(3H)-one 582.61  84

5-amino-3-(2-(4-(2-fluoro- 4-(((3S,4S)-4- hydroxytetrahydrofuran-3-yl)oxy)phenyl)piperazin-1- yl)ethyl)-8-(furan-2- yl)thiazolo[5,4-e][1,2,4]triazolo[1,5- c]pyrimidin-2(3H)-one 582.61  85

5-amino-3-(2-(4-(2-fluoro- 4-(2-hydroxy-2- methylpropoxy)phenyl)piper-azin-1-yl)ethyl)-8-(furan-2- yl)thiazolo[5,4- e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one 568.62  86

5-amino-3-(2-(4-(2-fluoro- 4-(2-hydroxypropan-2- yl)phenyl)piperazin-1-yl)ethyl)-8-(furan-2- yl)thiazolo[5,4- e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one 538.60  87

5-amino-3-(2-(4-(2-fluoro- 4-(3,3,3-trifluoro-2- hydroxypropoxy)phenyl)piperazin-1-yl)ethyl)-8-(furan- 2-yl)thiazolo[5,4-e][1,2,4]triazolo[1,5- c]pyrimidin-2(3H)-one 608.57  88

5-amino-3-(2-(4-(2-fluoro- 5-(2- hydroxyethoxy)phenyl)piperazin-1-yl)ethyl)- 8-(furan-2- yl)thiazolo[5,4-e][1,2,4]triazolo[1,5- c]pyrimidin-2(3H)-one 540.57  89

5-amino-3-(2-(4-(2,4- difluoro-5-(morpholin-2- ylmethoxy)phenyl)piperazin- 1-yl)ethyl)-8-(furan-2- yl)thiazolo[5,4-e][1,2,4]triazolo[1,5- c]pyrimidin-2(3H)-one 613.64  90

5-amino-3-(2-(4-(2,4- difluoro-5-(morpholin-3- ylmethoxy)phenyl)piperazin- 1-yl)ethyl)-8-(furan-2- yl)thiazolo[5,4-e][1,2,4]triazolo[1,5- c]pyrimidin-2(3H)-one 613.64  91

5-amino-3-(2-(4-(2,4- difluoro-5-(((3S,4S)-4- fluoropyrrolidin-3-yl)oxy)phenyl)piperazin-1- yl)ethyl)-8-(furan-2- yl)thiazolo[5,4-e][1,2,4]triazolo[1,5- c]pyrimidin-2(3H)-one 601.60  92

5-amino-3-(2-(4-(2,4- difluoro-5-(((3S,4S)-4- fluoropyrrolidin-3-yl)oxy)phenyl)piperazin-1- yl)ethyl)-8-(furan-2- yl)thiazolo[5,4-e][1,2,4]triazolo[1,5- c]pyrimidin-2(3H)-one 601.60  93

5-amino-3-(2-(4-(2,4- difluoro-5-(((3R,4S)-4- fluoropyrrolidin-3-yl)oxy)phenyl)piperazin-1- yl)ethyl)-8-(furan-2- yl)thiazolo[5,4-e][1,2,4]triazolo[1,5- c]pyrimidin-2(3H)-one 601.60  94

5-amino-3-(2-(4-(2,4- difluoro-5-(((3S,4R)-4- fluoropyrrolidin-3-yl)oxy)phenyl)piperazin-1- yl)ethyl)-8-(furan-2- yl)thiazolo[5,4-e][1,2,4]triazolo[1,5- c]pyrimidin-2(3H)-one 601.60  95

(S)-5-amino-3-(2-(4-(2,4- difluoro-5-((2- oxopyrrolidin-3-yl)oxy)phenyl)piperazin-1- yl)ethyl)-8-(furan-2- yl)thiazolo[5,4-e][1,2,4]triazolo[1,5- c]pyrimidin-2(3H)-one 597.60  96

(R)-5-amino-3-(2-(4-(2,4- difluoro-5-((2- oxopyrrolidin-3-yl)oxy)phenyl)piperazin-1- yl)ethyl)-8-(furan-2- yl)thiazolo[5,4-e][1,2,4]triazolo[1,5- c]pyrimidin-2(3H)-one 597.60  97

2-(5-(4-(2-(5-amino-8- (furan-2-yl)-2- oxothiazolo[5,4-e][1,2,4]triazolo[1,5- c]pyrimidin-3(2H)- yl)ethyl)piperazin-1-yl)-2,4-difluorophenoxy)-N-(2- morpholinoethyl)acetamide 684.72  98

5-(4-(2-(5-amino-8-(furan- 2-yl)-2-oxothiazolo[5,4-e][1,2,4]triazolo[1,5- c]pyrimidin-3(2H)- yl)ethyl)piperazin-1-yl)-2,4-difluoro-N-(morpholin-3- ylmethyl)benzamide 640.66  99

5-amino-3-(2-(4-(2-fluoro- 4-(morpholin-3- ylmethoxy)phenyl)piperazin-1-yl)ethyl)-8-(furan-2- yl)thiazolo[5,4- e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one 595.65 100

5-amino-3-(2-(4-(2-fluoro- 4-(morpholin-2- ylmethoxy)phenyl)piperazin-1-yl)ethyl)-8-(furan-2- yl)thiazolo[5,4- e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one 595.65 101

5-amino-3-(2-(4-(2-fluoro- 4-(((3R,4R)-4- fluoropyrrolidin-3-yl)oxy)phenyl)piperazin-1- yl)ethyl)-8-(furan-2- yl)thiazolo[5,4-e][1,2,4]triazolo[1,5- c]pyrimidin-2(3H)-one 583.61 102

5-amino-3-(2-(4-(2-fluoro- 4-(((3S,4S)-4- fluoropyrrolidin-3-yl)oxy)phenyl)piperazin-1- yl)ethyl)-8-(furan-2- yl)thiazolo[5,4-e][1,2,4]triazolo[1,5- c]pyrimidin-2(3H)-one 583.61 103

5-amino-3-(2-(4-(2-fluoro- 4-(((3R,4S)-4- fluoropyrrolidin-3-yl)oxy)phenyl)piperazin-1- yl)ethyl)-8-(furan-2- yl)thiazolo[5,4-e][1,2,4]triazolo[1,5- c]pyrimidin-2(3H)-one 583.61 104

5-amino-3-(2-(4-(2-fluoro- 4-(((3S,4R)-4- fluoropyrrolidin-3-yl)oxy)phenyl)piperazin-1- yl)ethyl)-8-(furan-2- yl)thiazolo[5,4-e][1,2,4]triazolo[1,5- c]pyrimidin-2(3H)-one 583.61 105

2-(4-(4-(2-(5-amino-8- (furan-2-yl)-2- oxothiazolo[5,4-e][1,2,4]triazolo[1,5- c]pyrimidin-3(2H)- yl)ethyl)piperazin-1-yl)-3-fluorophenoxy)-N-(2- morpholinoethyl)acetamide 666.73 106

4-(4-(2-(5-amino-8-(furan- 2-yl)-2-oxothiazolo[5,4-e][1,2,4]triazolo[1,5- c]pyrimidin-3(2H)- yl)ethyl)piperazin-1-yl)-3-fluoro-N-(2- morpholinoethyl)benzamide 636.70 107

4-(4-(2-(5-amino-8-(furan- 2-yl)-2-oxothiazolo[5,4-e][1,2,4]triazolo[1,5- c]pyrimidin-3(2H)- yl)ethyl)piperazin-1-yl)-3-fluoro-N-(morpholin-3- ylmethyl)benzamide 622.67 108

5-amino-3-(2-(4-(4- (azetidin-3- yloxy)phenyl)piperazin-1-yl)ethyl)-8-(furan-2- yl)thiazolo[5,4- e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one 533.61 109

(S)-5-amino-3-(2-(4-(2,4- difluoro-5- (methylsulfinyl)phenyl)piper-azin-1-yl)ethyl)-8-(furan-2- yl)thiazolo[5,4- e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one 560.60 110

(R)-5-amino-3-(2-(4-(2,4- difluoro-5- (methylsulfinyl)phenyl)piper-azin-1-yl)ethyl)-8-(furan-2- yl)thiazolo[5,4- e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one 560.60 111

5-amino-3-(2-(4-(2,4- difluoro-5-(((1s,4s)-1- oxidotetrahydro-2H-thiopyran-4- yl)oxy)phenyl)piperazin-1- yl)ethyl)-8-(furan-2-yl)thiazolo[5,4- e][1,2,4]triazolo[1,5- c]pyrimidin-2(3H)-one 630.69 112

5-amino-3-(2-(4-(2,4- difluoro-5-(((1r,4r)-1- oxidotetrahydro-2H-thiopyran-4- yl)oxy)phenyl)piperazin-1- yl)ethyl)-8-(furan-2-yl)thiazolo[5,4- e][1,2,4]triazolo[1,5- c]pyrimidin-2(3H)-one 630.69 113

(S)-5-(4-(2-(5-amino-8- (furan-2-yl)-2- oxothiazolo[5,4-e][1,2,4]triazolo[1,5- c]pyrimidin-3(2H)- yl)ethyl)piperazin-1-yl)-2,4-difluoro-N-(2- (methylsulfinyl)ethyl) benzamide 631.68 114

(R)-5-(4-(2-(5-amino-8- (furan-2-yl)-2- oxothiazolo[5,4-e][1,2,4]triazolo[1,5- c]pyrimidin-3(2H)- yl)ethyl)piperazin-1-yl)-2,4-difluoro-N-(2- (methylsulfinyl)ethyl) benzamide 631.68 115

(S)-5-(4-(2-(5-amino-8- (furan-2-yl)-2- oxothiazolo[5,4-e][1,2,4]triazolo[1,5- c]pyrimidin-3(2H)- yl)ethyl)piperazin-1-yl)-2,4-difluoro-N-methyl-N-(2- (methylsulfinyl)ethyl) benzamide 645.70 116

(R)-5-(4-(2-(5-amino-8- (furan-2-yl)-2- oxothiazolo[5,4-e][1,2,4]triazolo[1,5- c]pyrimidin-3(2H)- yl)ethyl)piperazin-1-yl)-2,4-difluoro-N-methyl-N-(2- (methylsulfinyl)ethyl) benzamide 645.70 117

5-amino-3-(2-(4-(2,4- difluoro-5-(1- oxidothiomorpholine-4-carbonyl)phenyl)piperazin- 1-yl)ethyl)-8-(furan-2- yl)thiazolo[5,4-e][1,2,4]triazolo[1,5- c]pyrimidin-2(3H)-one 643.69 118

5-amino-3-(2-(4-(2,4- difluoro-5-(1- oxidothiomorpholino)phen-yl)piperazin-1-yl)ethyl)-8- (furan-2-yl)thiazolo[5,4-e][1,2,4]triazolo[1,5- c]pyrimidin-2(3H)-one 615.68 119

(R)-5-amino-3-(2-(4-(2- fluoro-4- (methylsulfinyl)phenyl)piper-azin-1-yl)ethyl)-8-(furan-2- yl)thiazolo[5,4- e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one 542.61 120

(S)-5-amino-3-(2-(4-(2- fluoro-4- (methylsulfinyl)phenyl)piper-azin-1-yl)ethyl)-8-(furan-2- yl)thiazolo[5,4- e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one 542.61 121

5-amino-3-(2-(4-(2-fluoro- 4-(((1s,4s)-1- oxidotetrahydro-2H-thiopyran-4- yl)oxy)phenyl)piperazin-1- yl)ethyl)-8-(furan-2-yl)thiazolo[5,4- e][1,2,4]triazolo[1,5- c]pyrimidin-2(3H)-one 612.70 122

5-amino-3-(2-(4-(2-fluoro- 4-(((1r,4r)-1- oxidotetrahydro-2H-thiopyran-4- yl)oxy)phenyl)piperazin-1- yl)ethyl)-8-(furan-2-yl)thiazolo [5,4- e][1,2,4]triazolo[1,5- c]pyrimidin-2(3H)-one 612.70123

(S)-4-(4-(2-(5-amino-8- (furan-2-yl)-2- oxothiazolo[5,4-e][1,2,4]triazolo[1,5- c]pyrimidin-3(2H)- yl)ethyl)piperazin-1-yl)-3-fluoro-N-(2- (methylsulfinyl)ethyl) benzamide 613.69 124

(R)-4-(4-(2-(5-amino-8- (furan-2-yl)-2- oxothiazolo[5,4-e][1,2,4]triazolo[1,5- c]pyrimidin-3(2H)- yl)ethyl)piperazin-1-yl)-3-fluoro-N-(2- (methylsulfinyl)ethyl) benzamide 613.69 125

5-amino-3-(2-(4-(2-fluoro- 4-(1-oxidothiomorpholine- 4-carbonyl)phenyl)piperazin- 1-yl)ethyl)-8-(furan-2- yl)thiazolo[5,4-e][1,2,4]triazolo[1,5- c]pyrimidin-2(3H)-one 625.70 126

5-amino-3-(2-(4-(2-fluoro- 4-(1- oxidothiomorpholino)phen-yl)piperazin-1-yl)ethyl)-8- (furan-2-yl)thiazolo[5,4-e][1,2,4]triazolo[1,5- c]pyrimidin-2(3H)-one 597.69 127

(S)-5-amino-3-(2-(4-(5-(2,3- dihydroxypropoxy)-2,4-difluorophenyl)piperazin-1- yl)ethyl)-8-(furan-2- yl)thiazolo[5,4-e][1,2,4]triazolo[1,5- c]pyrimidin-2(3H)-one 588.59 128

(R)-5-amino-3-(2-(4-(5- (2,3-dihydroxypropoxy)- 2,4-difluorophenyl)piperazin-1- yl)ethyl)-8-(furan-2- yl)thiazolo[5,4-e][1,2,4]triazolo[1,5- c]pyrimidin-2(3H)-one 588.59 129

(S)-5-(4-(2-(5-amino-8- (furan-2-yl)-2- oxothiazolo[5,4-e][1,2,4]triazolo[1,5- c]pyrimidin-3(2H)- yl)ethyl)piperazin-1-yl)-N-(2,3-dihydroxypropyl)-2,4- difluorobenzamide 615.61 130

(R)-5-(4-(2-(5-amino-8- (furan-2-yl)-2- oxothiazolo[5,4-e][1,2,4]triazolo[1,5- c]pyrimidin-3(2H)- yl)ethyl)piperazin-1-yl)-N-(2,3-dihydroxypropyl)-2,4- difluorobenzamide 615.61 131

5-amino-3-(2-(4-(4- (azetidin-3-yloxy)-2- fluorophenyl)piperazin-1-yl)ethyl)-8-(furan-2- yl)thiazolo[5,4- e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one 551.60 132

5-amino-3-(2-(4-(5- (azetidin-3-yloxy)-2,4- difluorophenyl)piperazin-1-yl)ethyl)-8-(furan-2- yl)thiazolo[5,4- e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one 569.59 133

(S)-5-amino-3-(2-(4-(2,4- difluoro-5-(3- (methylsulfinyl)propoxy)phenyl)piperazin-1-yl)ethyl)- 8-(furan-2-yl)thiazolo[5,4-e][1,2,4]triazolo[1,5- c]pyrimidin-2(3H)-one 618.68

and pharmaceutically acceptable salts and solvates thereof.

In Table 1, the term “Cpd” means compound.

The compounds of Table 1 were named using ChemflioDraw® Ultra version12.0 (PerkinElmer).

In one embodiment, the compound of Formula (I) is selected from:

-   (R,S)-5-amino-3-(2-(4-(2,4-difluoro-5-(2-(methylsulfinyl)ethoxy)phenyl)piperazin-1-yl)ethyl)-8-(furan-2-yl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one    (compound 7);-   (+)-5-amino-3-(2-(4-(2,4-difluoro-5-(2-(methylsulfinyl)ethoxy)phenyl)piperazin-1-yl)ethyl)-8-(furan-2-yl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one    (compound 8a) and-   (−)-5-amino-3-(2-(4-(2,4-difluoro-5-(2-(methylsulfinyl)ethoxy)phenyl)piperazin-1-yl)ethyl)-8-(furan-2-yl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one    (compound 8b).

In a specific embodiment, the compound of Formula (I) is selected from:

-   (R,S)-5-amino-3-(2-(4-(2,4-difluoro-5-(2-(methylsulfinyl)ethoxy)phenyl)piperazin-1-yl)ethyl)-8-(furan-2-yl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one    (compound 7); and-   (+)-5-amino-3-(2-(4-(2,4-difluoro-5-(2-(methylsulfinyl)ethoxy)phenyl)piperazin-1-yl)ethyl)-8-(furan-2-yl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one    (compound 8a).

In preferred embodiment, the compound of Formula (I) is(+)-5-amino-3-(2-(4-(2,4-difluoro-5-(2-(methylsulfinyl)ethoxy)phenyl)piperazin-1-yl)ethyl)-8-(furan-2-yl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one(compound 8a).

In one embodiment, the present invention also relates to enantiomers,salts, solvates, polymorphs, multi-component complexes and liquidcrystals of compounds of Formula (I) and subformulae thereof.

In one embodiment, the present invention also relates to polymorphs andcrystal habits of compounds of Formula (I) and subformulae thereof,prodrugs and isomers thereof (including optical, geometric andtautomeric isomers) and isotopically-labeled compounds of Formula (I)and subformulae thereof.

The compounds of Formula (I) and subformulae thereof may contain anasymmetric center and thus may exist as different stereoisomeric forms.Accordingly, the present invention includes all possible stereoisomersand includes not only racemic compounds but the individual enantiomersand their non-racemic mixtures as well. When a compound is desired as asingle enantiomer, such may be obtained by stereospecific synthesis, byresolution of the final product or any convenient intermediate, or bychiral chromatographic methods as each are known in the art. Resolutionof the final product, an intermediate, or a starting material may beperformed by any suitable method known in the art.

The compounds of the invention may be in the form of pharmaceuticallyacceptable salts. Pharmaceutically acceptable salts of the compounds ofFormula (I) and subformulae thereof include the acid addition and basesalts thereof. Suitable acid addition salts are formed from acids whichform non-toxic salts. Examples include the acetate, adipate, aspartate,benzoate, besylate, bicarbonate/carbonate, bisulphate/sulphate, borate,camsylate, citrate, cyclamate, edisylate, esylate, formate, fumarate,gluceptate, gluconate, glucuronate, hexafluorophosphate, hibenzate,hydrochloride/chloride, hydrobromide/bromide, hydroiodide/iodide,isethionate, lactate, malate, maleate, malonate, mesylate,methylsulphate, naphthylate, 2-napsylate, nicotinate, nitrate, orotate,oxalate, palmitate, pamoate, phosphate/hydrogen phosphate/dihydrogenphosphate, pyroglutamate, saccharate, stearate, succinate, tannate,tartrate, tosylate, trifluoroacetate and xinofoate salts. Suitable basesalts are formed from bases which form non-toxic salts. Examples includethe aluminium, arginine, benzathine, calcium, choline, diethylamine,diolamine, glycine, lysine, magnesium, meglumine, olamine, potassium,sodium, tromethamine, 2-(diethylamino)ethanol, ethanolamine, morpholine,4-(2-hydroxyethyl)morpholine and zinc salts. Hemisalts of acids andbases may also be formed, for example, hemisulphate and hemicalciumsalts. Preferred, pharmaceutically acceptable salts includehydrochloride/chloride, hydrobromide/bromide, bisulphate/sulphate,nitrate, citrate, tosylate, esylate and acetate. In a particularlypreferred embodiment, the compounds of Formula (I) is under the form ofa HCl salt or esylate salt.

When the compounds of the invention contain an acidic group as well as abasic group the compounds of the invention may also form internal salts,and such compounds are within the scope of the invention. When thecompounds of the invention contain a hydrogen-donating heteroatom (e.g.NH), the invention also covers salts and/or isomers formed by transferof said hydrogen atom to a basic group or atom within the molecule.

Pharmaceutically acceptable salts of compounds of Formula (I) andsubformulae thereof may be prepared by one or more of these methods:

-   -   (i) by reacting the compound of Formula (I) with the desired        acid;    -   (ii) by reacting the compound of Formula (I) with the desired        base;    -   (iii) by removing an acid- or base-labile protecting group from        a suitable precursor of the compound of Formula (I) or by        ring-opening a suitable cyclic precursor, for example, a lactone        or lactam, using the desired acid; or    -   (iv) by converting one salt of the compound of Formula (I) to        another by reaction with an appropriate acid or by means of a        suitable ion exchange column.

All these reactions are typically carried out in solution. The salt, mayprecipitate from solution and be collected by filtration or may berecovered by evaporation of the solvent. The degree of ionization in thesalt may vary from completely ionized to almost non-ionized.

The compounds of the present invention may be administered in the formof pharmaceutically acceptable salts. The term “pharmaceuticallyacceptable salt” is intended to include all acceptable salts such asacetate, lactobionate, benzenesulfonate, laurate, benzoate, malate,bicarbonate, maleate, bisulfate, mandelate, bitartrate, mesylate,borate, methylbromide, bromide, methylnitrate, calcium edetate,methylsulfate, camsylate, mucate, carbonate, napsylate, chloride,nitrate, clavulanate, N-methylglucamine, citrate, ammonium salt,dihydrochloride, oleate, edetate, oxalate, edisylate, pamoate(embonate), estolate, palmitate, esylate, pantothenate, fumarate,phosphate/diphosphate, gluceptate, polygalacturonate, gluconate,salicylate, glutamate, stearate, glycollylarsanilate, sulfate,hexylresorcinate, subacetate, hydrabamine, succinate, hydrobromide,tannate, hydrochloride, tartrate, hydroxynaphthoate, teoclate, iodide,tosylate, isothionate, triethiodide, lactate, panoate, valerate, and thelike which can be used as a dosage form for modifying the solubility orhydrolysis characteristics or can be used in sustained release orpro-drug formulations. Depending on the particular functionality of thecompound of the present invention, pharmaceutically acceptable salts ofthe compounds of this invention include those formed from cations suchas sodium, potassium, aluminum, calcium, lithium, magnesium, zinc, andfrom bases such as ammonia, ethylenediamine, N-methyl-glutamine, lysine,arginine, ornithine, choline, N,N′-dibenzylethylene-diamine,chloroprocaine, diethanolamine, procaine, N-benzylphenethyl-amine,diethylamine, piperazine, tris(hydroxymethyl)aminomethane, andtetramethylammonium hydroxide.

These salts may be prepared by standard procedures, e.g. by reacting afree acid with a suitable organic or inorganic base. Where a basic groupis present, such as amino, an acidic salt, i.e. hydrochloride,hydrobromide, acetate, palmoate, esylate, tosylate and the like, can beused as the dosage form.

In addition, although generally, with respect to the salts of thecompounds of the invention, pharmaceutically acceptable salts arepreferred, it should be noted that the invention in its broadest sensealso included non-pharmaceutically acceptable salts, which may forexample be used in the isolation and/or purification of the compounds ofthe invention. For example, salts formed with optically active acids orbases may be used to form diastereoisomeric salts that can facilitatethe separation of optically active isomers of the compounds of Formula(I) above.

The compounds of the invention may be in the form of pharmaceuticallyacceptable solvates. Pharmaceutically acceptable solvates of thecompounds of Formula (I) and subformulae thereof contains stoichiometricor sub-stoichiometric amounts of one or more pharmaceutically acceptablesolvent molecule such as ethanol or water. The term “hydrate” refers towhen the said solvent is water.

The invention also generally covers all pharmaceutically acceptablepredrugs and prodrugs of the compounds of Formula (I) and subformulaethereof.

Also, in the case of an alcohol group being present, pharmaceuticallyacceptable esters can be employed, e.g. acetate, maleate,pivaloyloxymethyl, and the like, and those esters known in the art formodifying solubility or hydrolysis characteristics for use as sustainedrelease or prodrug formulations.

Pharmaceutical Composition

The invention thus relates to a pharmaceutical composition comprising aspharmaceutically active ingredient an A2A inhibitor, preferably being athiocarbamate derivative, more preferably a thiocarbamate derivative offormula (I) as described above, and at least one pharmaceuticallyacceptable carrier, diluent, excipient and/or adjuvant.

In one embodiment, the pharmaceutical composition of the inventioncomprises an A2A inhibitor, such as a thiocarbamate derivative offormula (I) as described above, and at least one lipid carrier. In oneembodiment, the lipid carrier is selected from lauroyl polyoxyl-32glycerides, D-α-tocopherol-polyethylene glycol-1000 succinate andmixtures thereof. In one embodiment, the lipid carrier is lauroylpolyoxyl-32 glycerides.

In another embodiment, the lipid carrier is-α-tocopherol-polyethyleneglycol-1000 succinate. In another embodiment, the lipid carrier is amixture of lauroyl polyoxyl-32 glycerides andD-α-tocopherol-polyethylene glycol-1000 succinate.

In one embodiment, the invention thus provides a pharmaceuticalcomposition comprising:

(a) a compound of Formula (I);

-   -   or a pharmaceutically acceptable salt or solvate thereof,        wherein R¹ and R² are as defined above;

(b) a lipid carrier selected from lauroyl polyoxyl-32 glycerides,D-α-tocopherol-polyethylene glycol-1000 succinate and mixtures thereof,and

(c) optionally one or more other pharmaceutically acceptable carrier,diluent, excipient and/or adjuvant.

In one embodiment, the invention provides a pharmaceutical compositioncomprising:

(a) a compound of Formula (I) or a pharmaceutically acceptable salt orsolvate thereof, wherein R¹ and R² are as defined above;

(b) lauroyl polyoxyl-32 glycerides; and

(c) optionally one or more other pharmaceutically acceptable carrier,diluent, excipient and/or adjuvant.

In another embodiment, the invention provides a pharmaceuticalcomposition comprising:

(a) a compound of Formula (I) or a pharmaceutically acceptable salt orsolvate thereof, wherein R¹ and R² are as defined above;

(b) D-α-tocopherol-polyethylene glycol-1000 succinate; and

(c) optionally one or more other pharmaceutically acceptable carrier,diluent, excipient and/or adjuvant.

Active Ingredient

The pharmaceutical composition of the invention thus comprises aspharmaceutically active ingredient a compound of Formula (I) or apharmaceutically acceptable salt or solvate thereof, wherein R¹ and R²are as defined above.

All the embodiment relative to the A2AR inhibitor detailed above applyto the pharmaceutical composition of the invention.

Lipid Carrier

The pharmaceutical composition of the invention comprises a lipidcarrier, preferably lauroyl polyoxyl-32 glycerides,D-α-tocopherol-polyethylene glycol-1000 succinate or a mixture thereof.

In one embodiment, the pharmaceutical composition of the inventioncomprises lauroyl polyoxyl-32 glycerides. This excipient corresponds toGelucire® 44/14 manufactured by Gattefossé (Saint-Priest—France). Thisexcipient is also known under the following references:

-   -   lauroyl polyoxyl-32 glycerides NF/USP (NF: National Formulary;        USP: US Pharmacopeia);    -   lauroyl macrogol-32 glycerides EP (European Pharmacopeia);    -   hydrogenated coconut PEG-32 esters (INCI);    -   CAS number 57107-95-6.

Gelucire® 44/14 corresponds to a well-defined multi-constituentsubstance constituted of mono-, di- and triglycerides and PEG-32 mono-and diesters of lauric acid (C₁₂). Gelucire® 44/14 has a melting pointranging from 42.5° C. to 47.5° C. (with a mean at 44° C.) and ahydrophilic/lipophilic balance (HLB) value of 14.

Gelucire® 44/14 is used in order to enhance wetting, dissolution,solubility and bioavailability of the active ingredient.

In another embodiment, the pharmaceutical composition of the inventioncomprises D-α-tocopherol-polyethylene glycol-1000 succinate. Thisexcipient corresponds to Vitamin E TPGS and is also known under thefollowing references:

-   -   D-α-Tocopherol polyethylene glycol-1000 succinate;    -   Tocophersolan;    -   Tocofersolan;    -   VEGS;    -   α-[4-[[(2R)-3,4-dihydro-2,5,7,8-tetramethyl-2-[(4R,8R)-4,8,12-trimethyltridecyl]-2H-1-benzopyran-6-yl]oxy]-1,4-dioxobutyl]-ω-hydroxy-poly(oxy-1,2-ethanediyl);    -   Vitamin E PEG succinate;    -   CAS number 9002-96-4.

Vitamin E TPGS corresponds to a well-defined substance constituted ofD-α-Tocopherol (Vitamin E) conjugated to polyethylene glycol 1000through a succinic acid linker and has a melting point ranging from 37°C. to 41° C. and a hydrophilic/lipophilic balance (HLB) value of 13.

Vitamin E TPGS is used in order to enhance wetting, dissolution,solubility and bioavailability of the active ingredient.

The pharmaceutical composition may comprise Vitamin E TPGS in additionor in place of lauroyl polyoxyl-32 glycerides.

Further Ingredients

The pharmaceutical composition of the invention may optionally compriseone or more other pharmaceutically acceptable carrier, diluent,excipient and/or adjuvant. Such suitable carrier, diluent, excipientand/or adjuvant for use in the preparation of the administration formswill be clear to the skilled person; reference is made to the latestedition of Remington's Pharmaceutical Sciences.

Especially, the pharmaceutical composition of the invention canoptionally contain such inactive substances that are commonly used inpharmaceutical formulations, such as for example cosolvents,antioxidants, surfactants, wetting agents, emulsifying agents, bufferingagents, pH modifying agents, preserving agents (or preservating agents),isotonifiers, stabilizing agents, granulating agents or binders,precipitation inhibitors, lubricants, disintegrants, glidants, diluentsor fillers, adsorbents, dispersing agents, suspending agents, bulkingagents, release agents, sweetening agents, flavoring agents, and thelike.

According to one embodiment, the pharmaceutical composition of theinvention comprises one or more pharmaceutically acceptable inactiveingredients selected from: caprylic acid, polyethylene glycol, propyleneglycol, ethanol, glycerol, dimethylsulfoxide, dimethylacetamide,dimethylisosorbide, cellulose derivatives (includinghydroxypropylmethylcellulose, methylcellulose, hydroxypropylcellulose,hydroxypropylmethylcellulose phthalate and hydroxypropylmethylcelluloseacetate succinate), cremophor RH40 (polyoxyl 40 hydrogenated castoroil), cremophor EL (polyoxyl 35 hydrogenated castor oil), polysorbate 20(polyoxyethylenesorbitan monolaurate), polysorbate 80(polyoxyethylenesorbitan monooleate), poloxamer 188 (poly(ethyleneglycol)-block-poly(propylene glycol)-block-poly(ethylene glycol)),poloxamer 407 (Poly(ethylene glycol)-block-poly(propyleneglycol)-block-poly(ethylene glycol)), vitamin E TPGS (vitamin Epolyethylene glycol succinate), solutol HS15 (polyoxyethylated12-hydroxystearic acid), labrasol (caprylocaproyl polyoxyl-8glycerides), labrafil M1944 (Oleoyl polyoxyl-6 glycerides),polyvinylpyrrolidone (also called povidone, preferablypolyvinylpyrrolidone K17, K19, K29-K32, K90), polyvinylpyrrolidonepolyvinylacetate copolymer, polyvinyl caprolactam-polyvinylacetate-polyethylene glycol graft copolymer (Soluplus®), polylactidepolyethylene glycol block copolymer, carboxymethylcellulose (Na/Ca),polyethylene glycol methyl ether-block-poly(D-L-lactide) copolymer,sodium lauryl sulfate, sodium docusate, propylene glycol monolaurate,propylene glycol dilaurate, propylene glycol monocaprylate, polyethyleneglycol 660 12-monostearate, poly(butylmethacrylate-co-(2-dimethylaminoethyl) methacrylate-co-methylmethacrylate) 1:2:1, sodium lauryl sulphate.

In a preferred embodiment, the pharmaceutical composition of theinvention comprises one or more pharmaceutically acceptable cosolvents.Preferably cosolvents are selected from caprylic acid, polyethyleneglycol (PEG), propylene glycol, ethanol, dimethylsulfoxide,dimethylacetamide, dimethylisosorbide and mixtures thereof. In aspecific embodiment, the pharmaceutical composition of the inventioncomprises caprylic acid and/or PEG. Advantageously, when the compositioncomprises PEG as cosolvent, PEG is of low molecular weight, preferablyPEG is PEG 400. In an alternative embodiment, when the compositioncomprises PEG, it is of a moderate molecular weight, preferably PEG3350.

In one embodiment, the pharmaceutical composition of the inventionfurther comprises one or more antioxidant; preferably the antioxidant isselected from butylated hydroxytoluene (BHT), butylated hydroxyanisole(BHA), citric acid, sodium metabisulfite, ascorbic acid, methionine andvitamin E; more preferably the antioxidant is BHT.

In some embodiments, surfactants are added, such as for examplepolyethylene glycols, polyoxyethylene sorbitan fatty acid esters,sorbitan esters, sodium docusate, sodium lauryl sulfate, polysorbates(20, 80, etc.), poloxamers (188, 407 etc.), pluronic polyols,polyoxyethylene sorbitan monoethers (TWEEN®-20, TWEEN®-80, etc.),vitamin E TPGS (Vitamin E polyethylene glycol succinate), cremophor RH40(polyoxyl 40 hydrogenated castor oil), cremophor EL (polyoxyl 35hydrogenated castor oil), polyethylene glycol 660 12-monostearate,solutol HS15 (Polyoxyethylated 12-hydroxystearic acid), labrasol(caprylocaproyl polyoxyl-8 glycerides), labrafil M1944 (Oleoylpolyoxyl-6 glycerides), polylactide polyethylene glycol block copolymer,polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graftcopolymer (Soluplus®).

In some embodiments, wetting agents are added, such as for examplesodium lauryl sulphate, vitamin E TPGS, sodium docusate, polysorbate 80,poloxamer 407. A preferred wetting agent is poloxamer 407.

In some embodiments, emulsifying agents are added, such as for examplecarbomer, carrageenan, lanolin, lecithin, mineral oil, oleic acid, oleylalcohol, pectin, poloxamer, polyoxyethylene sorbitan fatty acid esters,sorbitan esters, triethanolamine, propylene glycol monolaurate,propylene glycol dilaurate, propylene glycol monocaprylate. Preferredemulsifying agents are for example poloxamer, propylene glycolmonolaurate, propylene glycol dilaurate, and propylene glycolmonocaprylate.

In some embodiments, buffering agents are used to help to maintain thepH in the range that approximates physiological conditions Suitablebuffering agents include both organic and inorganic acids and saltsthereof, such as citrate buffers (e.g., monosodium citrate-disodiumcitrate mixture, citric acid-trisodium citrate mixture, citricacid-monosodium citrate mixture, etc.), succinate buffers (e.g.,succinic acid-monosodium succinate mixture, succinic acid-sodiumhydroxide mixture, succinic acid-disodium succinate mixture, etc.),tartrate buffers (e.g., tartaric acid-sodium tartrate mixture, tartaricacid-potassium tartrate mixture, tartaric acid-sodium hydroxide mixture,etc.), fumarate buffers (e.g., fumaric acid-monosodium fumarate mixture,fumaric acid-disodium fumarate mixture, monosodium fumarate-disodiumfumarate mixture, etc.), gluconate buffers (e.g., gluconic acid-sodiumglyconate mixture, gluconic acid-sodium hydroxide mixture, gluconicacid-potassium glyuconate mixture, etc.), oxalate buffer (e.g., oxalicacid-sodium oxalate mixture, oxalic acid-sodium hydroxide mixture,oxalic acid-potassium oxalate mixture, etc.), lactate buffers (e.g.,lactic acid-sodium lactate mixture, lactic acid-sodium hydroxidemixture, lactic acid-potassium lactate mixture, etc.) and acetatebuffers (e.g., acetic acid-sodium acetate mixture, acetic acid-sodiumhydroxide mixture, etc.). Additionally, phosphate buffers, histidinebuffers and trimethylamine salts such as Tris can be used.

In some embodiments, pH modifiers are added, such as for example sodiumhydroxide, sodium bicarbonate, magnesium oxide, potassium hydroxide,meglumine, sodium carbonate, citric acid, tartaric acid, ascorbic acid,fumaric acid, succinic acid and malic acid.

In some embodiments, preservatives agents are added to retard microbialgrowth. Suitable preservatives for use with the present disclosureinclude phenol, benzyl alcohol, meta-cresol, methyl paraben, propylparaben, octadecyldimethylbenzyl ammonium chloride, benzalconium halides(e.g., chloride, bromide, and iodide), hexamethonium chloride, and alkylparabens such as methyl or propyl paraben, catechol, resorcinol,cyclohexanol, and 3-pentanol.

In some embodiments, isotonifiers sometimes known as “stabilizers” areadded and include polyhydric sugar alcohols, for example trihydric orhigher sugar alcohols, such as glycerin, erythritol, arabitol, xylitol,sorbitol and mannitol. Stabilizers refer to a broad category ofexcipients which can range in function from a bulking agent to anadditive which solubilizes the therapeutic agent or helps to preventdenaturation or adherence to the container wall or helps to inhibit theprecipitation, particle growth or agglomeration of the activeingredient. Typical stabilizers can be polyhydric sugar alcohols(enumerated above); amino acids such as arginine, lysine, glycine,glutamine, asparagine, histidine, alanine, ornithine, L-leucine,2-phenylalanine, glutamic acid, threonine, etc.; organic sugars or sugaralcohols, such as lactose, trehalose, stachyose, mannitol, sorbitol,xylitol, ribitol, myoinisitol, galactitol, glycerol and the like,including cyclitols such as inositol; polyethylene glycol; amino acidpolymers; sulfur containing reducing agents, such as urea, glutathione,thioctic acid, sodium thioglycolate, thioglycerol, α-monothioglyceroland sodium thio sulfate; low molecular weight polypeptides (e.g.,peptides of 10 residues or fewer); proteins such as human serum albumin,bovine serum albumin, gelatin or immunoglobulins; hydrophylic polymers,such as polyvinylpyrrolidone; poloxamer 407; cellulose derivatives suchas hydroxypropylmethylcellulose, hydroxypropylmethylcellulose phthalateor hydroxypropylmethylcellulose acetate succinate;carboxymethylcellulose (Na/Ca); monosaccharides, such as xylose,mannose, fructose, glucose; disaccharides such as lactose, maltose,sucrose and trisaccacharides such as raffinose; polysaccharides such asdextran; polyethylene glycol methyl ether-block-poly(D-L-lactide)copolymer; poly(butyl methacrylate-co-(2-dimethylaminoethyl)methacrylate-co-methyl methacrylate) 1:2:1. Preferred stabilizers arefor example glycerol; polyethylene glycol; polyvinylpyrrolidone;cellulose derivatives such as hydroxypropylmethylcellulose,hydroxypropylmethylcellulose phthalate or hydroxypropylmethylcelluloseacetate succinate; carboxymethylcellulose (Na/Ca); polyethylene glycolmethyl ether-block-poly(D-L-lactide) copolymer; poly(butylmethacrylate-co-(2-dimethylaminoethyl) methacrylate-co-methylmethacrylate) 1:2:1; polyvinyl caprolactam-polyvinylacetate-polyethylene glycol graft copolymer and polyvinylpyrrolidonepolyvinylacetate copolymer.

In some embodiments granulating agent/binder(s) are added, such as forexample starch, gums (inclusive of natural, semisynthetic andsynthetic), microcrystalline cellulose, ethyl cellulose,methylcellulose, hydroxypropylcellulose, polymers such as povidone,polyvinylpyrrolidone polyvinylacetate copolymer and the like. Preferredgranulating agents are for example methylcellulose,hydroxypropylcellulose, povidone and polyvinylpyrrolidonepolyvinylacetate copolymer.

In some embodiments precipitation inhibitors are added, such as forexample water soluble derivatives of cellulose includinghydroxypropylmethylcellulose and methylcellulose, and water solublepolymers such as polyvinylpyrrolidone, polyvinylpyrrolidonepolyvinylacetate copolymer, polyvinyl caprolactam-polyvinylacetate-polyethylene glycol graft copolymer or poloxamer 407. Preferredprecipitation inhibitors are for example hydroxypropylmethylcelluloseand polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graftcopolymer.

In some embodiments lubricants are added, such as for example magnesiumstearate, glyceryl esters, behenoyl polyoxyl-8 glycerides Nf (CompritolHD5 ATO), sodium stearyl fumarate and the like.

In some embodiments disintegrants are added, such as for examplesynthetics like sodium starch glycolate, cross povidone, crosscarmellose sodium, kollidon CL, and natural origin such as locust beangum and the like.

In some embodiments glidants are added, such as for example talc,magnesium stearate, colloidal silicon dioxide, starch and the like.

In some embodiments diluents (or fillers) are added, such as for exampledextrose, lactose, mannitol, microcrystalline cellulose, sorbitol,sucrose, dibasic calcium phosphate, calcium sulphate dehydrate, starchand the like.

In some embodiments adsorbents are added, such as for example silicondioxide, purified aluminium silicate and the like.

In some embodiments, the pharmaceutical composition of the invention isin the form of tablets and tableting excipients are added, such as forexample granulating agents, binders, lubricants, disintegrants,glidants, diluents, adsorbents and the like.

In some embodiments the pharmaceutical composition of the invention isin the form of capsules, in which the capsule shells are constructedfrom gelatin or from non-animal derived products such as cellulose andits derivatives such as hydroxypropylmethylcellulose. Other ingredientsmay be included in the capsule shells such as polyethyleneglycol to actas plasticizer; pigments such as titanium dioxide or iron oxide toprovide opacity and colour differentiation; lubricants such as carnaubawax; gelling agents such as carrageenan and wetting agents such assodium lauryl sulphate. In one embodiment, the pharmaceuticalcomposition of the invention is formulated as capsules, wherein thecapsule shells are constructed from gelatin and wherein additionalcomponents are optionally included in the capsule shells, such as forexample polyethylene glycol and sodium lauryl sulphate.

Amounts

In one embodiment, the pharmaceutical composition of the inventioncomprises an amount of compound of Formula (I) ranging from 1% to 20% inweight to the total weight of the composition (w/w). Preferably thepharmaceutical composition of the invention comprises an amount ofcompound of Formula (I) ranging from 5% to 15% w/w, preferably from 8%to 12% w/w, more preferably from 9% to 11% w/w, more preferably about10% w/w.

In one embodiment, the pharmaceutical composition of the inventioncomprises an amount of lipid carrier ranging from 55% to 99% in weightto the total weight of the composition (w/w). Preferably thepharmaceutical composition of the invention comprises an amount of lipidcarrier ranging from 60% to 95% w/w, preferably from 65% to 90% w/w,more preferably from 70% to 90% w/w, about 70% w/w, about 71% w/w, about72% w/w, about 73% w/w, about 74% w/w, about 75% w/w, about 76% w/w,about 77% w/w, about 78% w/w, about 79% w/w, about 80% w/w, about 81%w/w, about 82% w/w, about 83% w/w, about 84% w/w, about 85% w/w. about86% w/w, about 87% w/w, about 88% w/w, about 89% w/w, about 90% w/w.

In one embodiment, the pharmaceutical composition of the inventioncomprises an amount of lauroyl polyoxyl-32 glycerides ranging from 55%to 99% in weight to the total weight of the composition (w/w).Preferably the pharmaceutical composition of the invention comprises anamount of lauroyl polyoxyl-32 glycerides ranging from 60% to 95% w/w,preferably from 65% to 90% w/w, more preferably from 70% to 90% w/w,more preferably about 70% w/w, about 71% w/w, about 72% w/w, about 73%w/w, about 74% w/w, about 75% w/w, about 76% w/w, about 77% w/w, about78% w/w, about 79% w/w, about 80% w/w, about 81% w/w, about 82% w/w,about 83% w/w, about 84% w/w, about 85% w/w, about 86% w/w, about 87%w/w, about 88% w/w, about 89% w/w, about 90% w/w.

In one embodiment, the pharmaceutical composition of the inventioncomprises an amount of D-α-tocopherol-polyethylene glycol-1000 succinateranging from 55% to 99% in weight to the total weight of the composition(w/w). Preferably the pharmaceutical composition of the inventioncomprises an amount of D-α-tocopherol-polyethylene glycol-1000 succinateranging from 60% to 95% w/w, preferably from 65% to 90% w/w, morepreferably from 70% to 90% w/w, more preferably about 70% w/w, about 71%w/w, about 72% w/w, about 73% w/w, about 74% w/w, about 75% w/w, about76% w/w, about 77% w/w, about 78% w/w, about 79% w/w, about 80% w/w,about 81% w/w, about 82% w/w, about 83% w/w, about 84% w/w, about 85%w/w, about 86% w/w, about 87% w/w, about 88% w/w, about 89% w/w, about90% w/w.

In one embodiment, the pharmaceutical composition of the invention maycomprise PEG 400, in an amount ranging from 0% to 30% in weight to thetotal weight of the composition (w/w). Preferably the pharmaceuticalcomposition of the invention comprises an amount of PEG 400 ranging from5% to 30% w/w, preferably from 10% to 25% w/w, more preferably from 15%to 20% w/w, more preferably about 15% w/w, about 16% w/w, about 17% w/w,about 18% w/w, about 19% w/w, about 20% w/w, more preferably about 18%w/w.

In one embodiment, the pharmaceutical composition of the invention maycomprise PEG 3350, in an amount ranging from 0% to 30% in weight to thetotal weight of the composition (w/w). Preferably the pharmaceuticalcomposition of the invention comprises an amount of PEG 3350 rangingfrom 5% to 30% w/w, preferably from 10% to 25% w/w, more preferably from15% to 20% w/w, more preferably about 15% w/w, about 16% w/w, about 17%w/w, about 18% w/w, about 19% w/w, about 20% w/w, more preferably about18% w/w.

In one embodiment, the pharmaceutical composition of the invention maycomprise caprylic acid, in an amount ranging from 0% to 20% in weight tothe total weight of the composition (w/w). Preferably the pharmaceuticalcomposition of the invention comprises an amount of caprylic acidranging from 1% to 20% w/w, preferably from 3% to 15% w/w, morepreferably from 5% to 10% w/w, more preferably about 5% w/w, about 6%w/w, about 7% w/w, about 8% w/w, about 9% w/w, more preferably about 9%w/w.

In one embodiment, the pharmaceutical composition of the invention maycomprise an antioxidant agent, preferably BHT, in an amount ranging from0% to 5% in weight to the total weight of the composition (w/w).Preferably the pharmaceutical composition of the invention comprises anamount of BHT ranging from 0.001% to 5% w/w, preferably from 0.005% to1% w/w, more preferably from 0.01% to 0.5% w/w, more preferably about0.010% w/w, about 0.05% w/w, about 0.10% w/w, about 0.150% w/w, about0.20% w/w, about 0.25% w/w, about 0.30% w/w, about 0.40% w/w, about0.50% w/w, more preferably about 0.10% w/w.

In one embodiment, the pharmaceutical composition of the invention maycomprise a wetting agent, preferably sodium lauryl sulphate (SLS), in anamount ranging from 0% to 10% in weight to the total weight of thecomposition (w/w). Preferably the pharmaceutical composition of theinvention comprises an amount of SLS ranging from 0.5% to 5% w/w,preferably from 0.5% to 2% w/w, more preferably from 0.5% to 1.5% w/w,more preferably about 1.0% w/w.

In one embodiment, the pharmaceutical composition of the invention maycomprise a precipitation inhibitor, preferablyhydroxypropylmethylcellulose, in an amount ranging from 0% to 10% inweight to the total weight of the composition (w/w). Preferably thepharmaceutical composition of the invention comprises an amount ofhydroxypropylmethylcellulose ranging from 0.5% to 5% w/w, preferablyfrom 0.5% to 2% w/w, more preferably from 0.5% to 1.5% w/w, morepreferably about 1% w/w.

In one embodiment the pharmaceutical composition of the invention maycomprise an alternative precipitation inhibitor, preferably polyvinylcaprolactam-polyvinyl acetate-polyethylene glycol graft copolymer in anamount ranging from 0% to 10% in weight to the total weight of thecomposition (w/w). Preferably the pharmaceutical composition of theinvention comprises an amount of polyvinyl caprolactam-polyvinylacetate-polyethylene glycol graft copolymer ranging from 0.5% to 5% w/w,preferably from 0.5% to 2% w/w, more preferably from 0.5% to 1.5% w/w,more preferably about 1.0% w/w.

In one embodiment the pharmaceutical composition of the invention maycomprise an alternative precipitation inhibitor, preferably poloxamer407 in an amount ranging from 0% to 10% in weight to the total weight ofthe composition (w/w). Preferably the pharmaceutical composition of theinvention comprises an amount of poloxamer 407 ranging from 0.5% to 5%w/w, preferably from 0.5% to 2% w/w, more preferably from 0.5% to 1.5%w/w, more preferably about 1.0% w/w.

In one embodiment the pharmaceutical composition of the invention maycomprise an alternative precipitation inhibitor, preferablypolyvinylpyrrolidone polyvinyl acetate copolymer in an amount rangingfrom 0% to 10% in weight to the total weight of the composition (w/w).Preferably the pharmaceutical composition of the invention comprises anamount of polyvinylpyrrolidone polyvinyl acetate ranging from 0.5% to 5%w/w, preferably from 0.5% to 2% w/w, more preferably from 0.5% to 1.5%w/w, more preferably about 1.0% w/w.

In one embodiment, the pharmaceutical composition of the inventioncomprises:

a) from 1% to 20% in weight to the total weight of the composition (w/w)of compound of Formula (I); preferably from 5% to 15% w/w, morepreferably from 8% to 12% w/w, more preferably from 9% to 11% w/w, morepreferably about 10% w/w; and

b) from 55% to 99% w/w of lauroyl polyoxyl-32 glycerides, preferablyfrom 60% to 95% w/w, preferably from 65% to 90% w/w, more preferablyfrom 70% to 90% w/w, more preferably about 70% w/w, about 71% w/w, about72% w/w, about 73% w/w, about 74% w/w, about 75% w/w, about 76% w/w,about 77% w/w, about 78% w/w, about 79% w/w, about 80% w/w, about 81%w/w, about 82% w/w, about 83% w/w, about 84% w/w, about 85% w/w, about86% w/w, about 87% w/w, about 88% w/w, about 89% w/w, about 90% w/w.

In one embodiment, the pharmaceutical composition of the inventioncomprises:

a) from 1% to 20% in weight to the total weight of the composition (w/w)of compound of Formula (I); preferably from 5% to 15% w/w, morepreferably from 8% to 12% w/w, more preferably from 9% to 11% w/w, morepreferably about 10% w/w;

b) from 55% to 99% w/w of lauroyl polyoxyl-32 glycerides, preferablyfrom 60% to 95% w/w, preferably from 65% to 90% w/w, more preferablyfrom 70% to 90% w/w, more preferably about 70% w/w, about 71% w/w, about72% w/w, about 73% w/w, about 74% w/w, about 75% w/w, about 76% w/w,about 77% w/w, about 78% w/w, about 79% w/w, about 80% w/w, about 81%w/w, about 82% w/w, about 83% w/w, about 84% w/w, about 85% w/w, about86% w/w, about 87% w/w, about 88% w/w, about 89% w/w, about 90% w/w;

c) from 0% to 30% w/w of PEG 400, preferably from 5% to 30% w/w,preferably from 10% to 25% w/w, more preferably from 15% to 20% w/w,more preferably about 15% w/w, about 16% w/w, about 17% w/w, about 18%w/w, about 19% w/w, about 20% w/w, more preferably about 18% w/w; and

d) from 0% to 5% w/w of BHT, preferably from 0.001% to 5% w/w,preferably from 0.005% to 1% w/w, more preferably from 0.01% to 0.5%w/w, more preferably about 0.010% w/w, about 0.05% w/w, about 0.10% w/w,about 0.150% w/w, about 0.20% w/w, about 0.25% w/w, about 0.30% w/w,about 0.40% w/w, about 0.50% w/w, more preferably about 0.10% w/w to thetotal weight of the composition (w/w).

In one embodiment, the pharmaceutical composition of the inventioncomprises:

a) from 1% to 20% in weight to the total weight of the composition (w/w)of compound of Formula (I); preferably from 5% to 15% w/w, morepreferably from 8% to 12% w/w, more preferably from 9% to 11% w/w, morepreferably about 10% w/w;

b) from 55% to 99% w/w of lauroyl polyoxyl-32 glycerides, preferablyfrom 60% to 95% w/w, preferably from 65% to 90% w/w, more preferablyfrom 70% to 90% w/w, more preferably about 70% w/w, about 71% w/w, about72% w/w, about 73% w/w, about 74% w/w, about 75% w/w, about 76% w/w,about 77% w/w, about 78% w/w, about 79% w/w, about 80% w/w, about 81%w/w, about 82% w/w, about 83% w/w, about 84% w/w, about 85% w/w, about86% w/w, about 87% w/w, about 88% w/w, about 89% w/w, about 90% w/w;

c) from 0% to 30% w/w of PEG 3350, preferably from 5% to 30% w/w,preferably from 10% to 25% w/w, more preferably from 15% to 20% w/w,more preferably about 15% w/w, about 16% w/w, about 17% w/w, about 18%w/w, about 19% w/w, about 20% w/w, more preferably about 18% w/w; and

d) from 0% to 5% w/w of BHT, preferably from 0.001% to 5% w/w,preferably from 0.005% to 1% w/w, more preferably from 0.01% to 0.5%w/w, more preferably about 0.010% w/w, about 0.05% w/w, about 0.10% w/w,about 0.150% w/w, about 0.20% w/w, about 0.25% w/w, about 0.30% w/w,about 0.40% w/w, about 0.50% w/w, more preferably about 0.10% w/w to thetotal weight of the composition (w/w).

In one embodiment, the pharmaceutical composition of the inventioncomprises:

a) from 1% to 20% in weight to the total weight of the composition (w/w)of compound of Formula (I); preferably from 5% to 15% w/w, morepreferably from 8% to 12% w/w, more preferably from 9% to 11% w/w, morepreferably about 10% w/w;

b) from 55% to 99% w/w of lauroyl polyoxyl-32 glycerides, preferablyfrom 60% to 95% w/w, preferably from 65% to 90% w/w, more preferablyfrom 70% to 90% w/w, more preferably about 70% w/w, about 71% w/w, about72% w/w, about 73% w/w, about 74% w/w, about 75% w/w, about 76% w/w,about 77% w/w, about 78% w/w, about 79% w/w, about 80% w/w, about 81%w/w, about 82% w/w, about 83% w/w, about 84% w/w, about 85% w/w, about86% w/w, about 87% w/w, about 88% w/w, about 89% w/w, about 90% w/w;

c) from 0% to 20% w/w of caprylic acid, preferably from 1% to 20% w/w,preferably from 3% to 15% w/w, more preferably from 5% to 10% w/w, morepreferably about 5% w/w, about 6% w/w, about 7% w/w, about 8% w/w, about9% w/w, more preferably about 9% w/w; and

d) from 0% to 5% w/w of BHT, preferably from 0.001% to 5% w/w,preferably from 0.005% to 1% w/w, more preferably from 0.01% to 0.5%w/w, more preferably about 0.010% w/w, about 0.05% w/w, about 0.10% w/w,about 0.150% w/w, about 0.20% w/w, about 0.25% w/w, about 0.30% w/w,about 0.40% w/w, about 0.50% w/w, more preferably about 0.10% w/w to thetotal weight of the composition (w/w).

In one embodiment, the pharmaceutical composition of the inventioncomprises:

a) from 1% to 20% in weight to the total weight of the composition (w/w)of compound of Formula (I) in the form of a salt, preferably as eitherthe HCl salt or the esylate salt; preferably from 5% to 15% w/w, morepreferably from 8% to 12% w/w, more preferably from 9% to 11% w/w, morepreferably about 10% w/w;

b) from 55% to 99% w/w of lauroyl polyoxyl-32 glycerides, preferablyfrom 60% to 95% w/w, preferably from 65% to 90% w/w, more preferablyfrom 70% to 90% w/w, more preferably about 70% w/w, about 71% w/w, about72% w/w, about 73% w/w, about 74% w/w, about 75% w/w, about 76% w/w,about 77% w/w, about 78% w/w, about 79% w/w, about 80% w/w, about 81%w/w, about 82% w/w, about 83% w/w, about 84% w/w, about 85% w/w, about86% w/w, about 87% w/w, about 88% w/w, about 89% w/w, about 90% w/w;

c) from 0% to 30% w/w of PEG400, preferably from 5% to 30% w/w,preferably from 10% to 25% w/w, more preferably from 15% to 20% w/w,more preferably about 15% w/w, about 16% w/w, about 17% w/w, about 18%w/w, about 19% w/w, about 20% w/w, more preferably about 18% w/w; and

d) from 0% to 5% w/w of BHT, preferably from 0.001% to 5% w/w,preferably from 0.005% to 1% w/w, more preferably from 0.01% to 0.5%w/w, more preferably about 0.010% w/w, about 0.05% w/w, about 0.10% w/w,about 0.150% w/w, about 0.20% w/w, about 0.25% w/w, about 0.30% w/w,about 0.40% w/w, about 0.50% w/w, more preferably about 0.10% w/w to thetotal weight of the composition (w/w).

In one embodiment, the pharmaceutical composition of the inventioncomprises:

a) from 1% to 20% in weight to the total weight of the composition (w/w)of compound of Formula (I) in the form of a salt, preferably as eitherthe HCl salt or the esylate salt; preferably from 5% to 15% w/w, morepreferably from 8% to 12% w/w, more preferably from 9% to 11% w/w, morepreferably about 10% w/w;

b) from 55% to 99% w/w of lauroyl polyoxyl-32 glycerides, preferablyfrom 60% to 95% w/w, preferably from 65% to 90% w/w, more preferablyfrom 70% to 90% w/w, more preferably about 70% w/w, about 71% w/w, about72% w/w, about 73% w/w, about 74% w/w, about 75% w/w, about 76% w/w,about 77% w/w, about 78% w/w, about 79% w/w, about 80% w/w, about 81%w/w, about 82% w/w, about 83% w/w, about 84% w/w, about 85% w/w, about86% w/w, about 87% w/w, about 88% w/w, about 89% w/w, about 90% w/w;

c) from 0% to 30% w/w of PEG3350, preferably from 5% to 30% w/w,preferably from 10% to 25% w/w, more preferably from 15% to 20% w/w,more preferably about 15% w/w, about 16% w/w, about 17% w/w, about 18%w/w, about 19% w/w, about 20% w/w, more preferably about 18% w/w; and

d) from 0% to 5% w/w of BHT, preferably from 0.001% to 5% w/w,preferably from 0.005% to 1% w/w, more preferably from 0.01% to 0.5%w/w, more preferably about 0.010% w/w, about 0.05% w/w, about 0.10% w/w,about 0.150% w/w, about 0.20% w/w, about 0.25% w/w, about 0.30% w/w,about 0.40% w/w, about 0.50% w/w, more preferably about 0.10% w/w to thetotal weight of the composition (w/w).

In one embodiment, the pharmaceutical composition of the inventioncomprises:

a) from 1% to 20% in weight to the total weight of the composition (w/w)of compound of Formula (I); preferably from 5% to 15% w/w, morepreferably from 8% to 12% w/w, more preferably from 9% to 11% w/w, morepreferably about 10% w/w; and

b) from 55% to 99% w/w of Vitamin E TPGS, preferably from 60% to 95%w/w, preferably from 65% to 90% w/w, more preferably from 70% to 90%w/w, more preferably about 70% w/w, about 71% w/w, about 72% w/w, about73% w/w, about 74% w/w, about 75% w/w, about 76% w/w, about 77% w/w,about 78% w/w, about 79% w/w, about 80% w/w, about 81% w/w, about 82%w/w, about 83% w/w, about 84% w/w, about 85% w/w, about 86% w/w, about87% w/w, about 88% w/w, about 89% w/w, about 90% w/w.

In one embodiment, the pharmaceutical composition of the inventioncomprises:

a) from 1% to 20% in weight to the total weight of the composition (w/w)of compound of Formula (I); preferably from 5% to 15% w/w, morepreferably from 8% to 12% w/w, more preferably from 9% to 11% w/w, morepreferably about 10% w/w;

b) from 55% to 99% w/w of Vitamin E TPGS, preferably from 60% to 95%w/w, preferably from 65% to 90% w/w, more preferably from 70% to 90%w/w, more preferably about 70% w/w, about 71% w/w, about 72% w/w, about73% w/w, about 74% w/w, about 75% w/w, about 76% w/w, about 77% w/w,about 78% w/w, about 79% w/w, about 80% w/w, about 81% w/w, about 82%w/w, about 83% w/w, about 84% w/w, about 85% w/w, about 86% w/w, about87% w/w, about 88% w/w, about 89% w/w, about 90% w/w;

c) from 0% to 30% w/w of PEG 400, preferably from 5% to 30% w/w,preferably from 10% to 25% w/w, more preferably from 15% to 20% w/w,more preferably about 15% w/w, about 16% w/w, about 17% w/w, about 18%w/w, about 19% w/w, about 20% w/w, more preferably about 18% w/w; and

d) from 0% to 5% w/w of BHT, preferably from 0.001% to 5% w/w,preferably from 0.005% to 1% w/w, more preferably from 0.01% to 0.5%w/w, more preferably about 0.010% w/w, about 0.05% w/w, about 0.10% w/w,about 0.150% w/w, about 0.20% w/w, about 0.25% w/w, about 0.30% w/w,about 0.40% w/w, about 0.50% w/w, more preferably about 0.10% w/w to thetotal weight of the composition (w/w).

In one embodiment, the pharmaceutical composition of the inventioncomprises:

a) from 1% to 20% in weight to the total weight of the composition (w/w)of compound of Formula (I); preferably from 5% to 15% w/w, morepreferably from 8% to 12% w/w, more preferably from 9% to 11% w/w, morepreferably about 10% w/w;

b) from 55% to 99% w/w of Vitamin E TPGS, preferably from 60% to 95%w/w, preferably from 65% to 90% w/w, more preferably from 70% to 90%w/w, more preferably about 70% w/w, about 71% w/w, about 72% w/w, about73% w/w, about 74% w/w, about 75% w/w, about 76% w/w, about 77% w/w,about 78% w/w, about 79% w/w, about 80% w/w, about 81% w/w, about 82%w/w, about 83% w/w, about 84% w/w, about 85% w/w, about 86% w/w, about87% w/w, about 88% w/w, about 89% w/w, about 90% w/w;

c) from 0% to 30% w/w of PEG 3350, preferably from 5% to 30% w/w,preferably from 10% to 25% w/w, more preferably from 15% to 20% w/w,more preferably about 15% w/w, about 16% w/w, about 17% w/w, about 18%w/w, about 19% w/w, about 20% w/w, more preferably about 18% w/w; and

d) from 0% to 5% w/w of BHT, preferably from 0.001% to 5% w/w,preferably from 0.005% to 1% w/w, more preferably from 0.01% to 0.5%w/w, more preferably about 0.010% w/w, about 0.05% w/w, about 0.10% w/w,about 0.150% w/w, about 0.20% w/w, about 0.25% w/w, about 0.30% w/w,about 0.40% w/w, about 0.50% w/w, more preferably about 0.10% w/w to thetotal weight of the composition (w/w).

In one embodiment, the pharmaceutical composition of the inventioncomprises:

a) from 1% to 20% in weight to the total weight of the composition (w/w)of compound of Formula (I); preferably from 5% to 15% w/w, morepreferably from 8% to 12% w/w, more preferably from 9% to 11% w/w, morepreferably about 10% w/w;

b) from 55% to 99% w/w of Vitamin E TPGS, preferably from 60% to 95%w/w, preferably from 65% to 90% w/w, more preferably from 70% to 90%w/w, more preferably about 70% w/w, about 71% w/w, about 72% w/w, about73% w/w, about 74% w/w, about 75% w/w, about 76% w/w, about 77% w/w,about 78% w/w, about 79% w/w, about 80% w/w, about 81% w/w, about 82%w/w, about 83% w/w, about 84% w/w, about 85% w/w, about 86% w/w, about87% w/w, about 88% w/w, about 89% w/w, about 90% w/w;

c) from 0% to 20% w/w of caprylic acid, preferably from 1% to 20% w/w,preferably from 3% to 15% w/w, more preferably from 5% to 10% w/w, morepreferably about 5% w/w, about 6% w/w, about 7% w/w, about 8% w/w, about9% w/w, more preferably about 9% w/w; and

d) from 0% to 5% w/w of BHT, preferably from 0.001% to 5% w/w,preferably from 0.005% to 1% w/w, more preferably from 0.01% to 0.5%w/w, more preferably about 0.010% w/w, about 0.05% w/w, about 0.10% w/w,about 0.150% w/w, about 0.20% w/w, about 0.25% w/w, about 0.30% w/w,about 0.40% w/w, about 0.50% w/w, more preferably about 0.10% w/w to thetotal weight of the composition (w/w).

In one embodiment, the pharmaceutical composition of the inventioncomprises:

a) from 1% to 20% in weight to the total weight of the composition (w/w)of compound of Formula (I) in the form of a salt, preferably as eitherthe HCl salt or the esylate salt; preferably from 5% to 15% w/w, morepreferably from 8% to 12% w/w, more preferably from 9% to 11% w/w, morepreferably about 10% w/w;

b) from 55% to 99% w/w of Vitamin E TPGS, preferably from 60% to 95%w/w, preferably from 65% to 90% w/w, more preferably from 70% to 90%w/w, more preferably about 70% w/w, about 71% w/w, about 72% w/w, about73% w/w, about 74% w/w, about 75% w/w, about 76% w/w, about 77% w/w,about 78% w/w, about 79% w/w, about 80% w/w, about 81% w/w, about 82%w/w, about 83% w/w, about 84% w/w, about 85% w/w, about 86% w/w, about87% w/w, about 88% w/w, about 89% w/w, about 90% w/w;

c) from 0% to 30% w/w of PEG400, preferably from 5% to 30% w/w,preferably from 10% to 25% w/w, more preferably from 15% to 20% w/w,more preferably about 15% w/w, about 16% w/w, about 17% w/w, about 18%w/w, about 19% w/w, about 20% w/w, more preferably about 18% w/w; and

d) from 0% to 5% w/w of BHT, preferably from 0.001% to 5% w/w,preferably from 0.005% to 1% w/w, more preferably from 0.01% to 0.5%w/w, more preferably about 0.010% w/w, about 0.05% w/w, about 0.10% w/w,about 0.150% w/w, about 0.20% w/w, about 0.25% w/w, about 0.30% w/w,about 0.40% w/w, about 0.50% w/w, more preferably about 0.10% w/w to thetotal weight of the composition (w/w).

In one embodiment, the pharmaceutical composition of the inventioncomprises:

a) from 1% to 20% in weight to the total weight of the composition (w/w)of compound of Formula (I) in the form of a salt, preferably as eitherthe HCl salt or the esylate salt; preferably from 5% to 15% w/w, morepreferably from 8% to 12% w/w, more preferably from 9% to 11% w/w, morepreferably about 10% w/w;

b) from 55% to 99% w/w of Vitamin E TPGS, preferably from 60% to 95%w/w, preferably from 65% to 90% w/w, more preferably from 70% to 90%w/w, more preferably about 70% w/w, about 71% w/w, about 72% w/w, about73% w/w, about 74% w/w, about 75% w/w, about 76% w/w, about 77% w/w,about 78% w/w, about 79% w/w, about 80% w/w, about 81% w/w, about 82%w/w, about 83% w/w, about 84% w/w, about 85% w/w, about 86% w/w, about87% w/w, about 88% w/w, about 89% w/w, about 90% w/w;

c) from 0% to 30% w/w of PEG3350, preferably from 5% to 30% w/w,preferably from 10% to 25% w/w, more preferably from 15% to 20% w/w,more preferably about 15% w/w, about 16% w/w, about 17% w/w, about 18%w/w, about 19% w/w, about 20% w/w, more preferably about 18% w/w; and

d) from 0% to 5% w/w of BHT, preferably from 0.001% to 5% w/w,preferably from 0.005% to 1% w/w, more preferably from 0.01% to 0.5%w/w, more preferably about 0.010% w/w, about 0.05% w/w, about 0.10% w/w,about 0.150% w/w, about 0.20% w/w, about 0.25% w/w, about 0.30% w/w,about 0.40% w/w, about 0.50% w/w, more preferably about 0.10% w/w to thetotal weight of the composition (w/w).

In one embodiment, the pharmaceutical composition of the inventioncomprises:

a) from 5% to 15% w/w of compound of Formula (I);

b) from 70% to 90% w/w of lauroyl polyoxyl-32 glycerides;

c) from 10% to 25% w/w of PEG400; and

d) optionally from 0.01% to 0.5% w/w of BHT.

In one embodiment, the pharmaceutical composition of the inventioncomprises:

a) from 5% to 15% w/w of compound of Formula (I);

b) from 70% to 90% w/w of lauroyl polyoxyl-32 glycerides;

c) from 10% to 25% w/w of PEG400;

d) optionally from 0.01% to 0.5% w/w of BHT;

e) optionally from 0.5% to 10% w/w of SL S; and

f) optionally from 0.5% to 10% w/w of hydroxypropylmethylcellulose.

In one embodiment, the pharmaceutical composition of the inventioncomprises:

a) from 5% to 15% w/w of compound of Formula (I);

b) from 70% to 90% w/w of lauroyl polyoxyl-32 glycerides;

c) from 10% to 25% w/w of PEG400;

d) optionally from 0.01% to 0.5% w/w of BHT; and

e) optionally from 0.5% to 10% w/w of hydroxypropylmethylcellulose.

In one embodiment, the pharmaceutical composition of the inventioncomprises:

a) from 5% to 15% w/w of compound of Formula (I);

b) from 70% to 90% w/w of lauroyl polyoxyl-32 glycerides;

c) from 10% to 25% w/w of PEG400;

d) optionally from 0.01% to 0.5% w/w of BHT; and

e) optionally from 0.5% to 10% w/w of poloxamer 407.

In one embodiment, the pharmaceutical composition of the inventioncomprises:

a) from 5% to 15% w/w of compound of Formula (I);

b) from 70% to 90% w/w of lauroyl polyoxyl-32 glycerides;

c) from 10% to 25% w/w of PEG400;

d) optionally from 0.01% to 0.5% w/w of BHT; and

e) optionally from 0.5% to 10% w/w of polyvinyl caprolactam-polyvinylacetate-polyethylene glycol graft copolymer.

In one embodiment, the pharmaceutical composition of the inventioncomprises:

a) from 5% to 15% w/w of compound of Formula (I);

b) from 70% to 90% w/w of lauroyl polyoxyl-32 glycerides;

c) from 10% to 25% w/w of PEG400;

d) optionally from 0.01% to 0.5% w/w of BHT; and

e) optionally from 0.5% to 10% w/w of polyvinyl pyrrolidone polyvinylacetate copolymer.

In one embodiment, the pharmaceutical composition of the inventioncomprises:

a) from 5% to 15% w/w of compound of Formula (I);

b) from 70% to 90% w/w of lauroyl polyoxyl-32 glycerides;

c) from 10% to 25% w/w of PEG3350; and

d) optionally from 0.01% to 0.5% w/w of BHT.

In one embodiment, the pharmaceutical composition of the inventioncomprises:

a) from 5% to 15% w/w of compound of Formula (I);

b) from 70% to 90% w/w of lauroyl polyoxyl-32 glycerides;

c) from 10% to 25% w/w of PEG3350;

d) optionally from 0.01% to 0.5% w/w of BHT;

e) optionally from 0.5% to 10% w/w of SL S; and

f) optionally from 0.5% to 10% w/w of hydroxypropylmethylcellulose.

In one embodiment, the pharmaceutical composition of the inventioncomprises:

a) from 5% to 15% w/w of compound of Formula (I);

b) from 70% to 90% w/w of lauroyl polyoxyl-32 glycerides;

c) from 10% to 25% w/w of PEG3350;

d) optionally from 0.01% to 0.5% w/w of BHT; and

e) optionally from 0.5% to 10% w/w of hydroxypropylmethylcellulose.

In one embodiment, the pharmaceutical composition of the inventioncomprises:

a) from 5% to 15% w/w of compound of Formula (I);

b) from 70% to 90% w/w of lauroyl polyoxyl-32 glycerides;

c) from 10% to 25% w/w of PEG3350;

d) optionally from 0.01% to 0.5% w/w of BHT; and

e) optionally from 0.5% to 10% w/w of poloxamer 407/In one embodiment,the pharmaceutical composition of the invention comprises:

a) from 5% to 15% w/w of compound of Formula (I);

b) from 70% to 90% w/w of lauroyl polyoxyl-32 glycerides;

c) from 10% to 25% w/w of PEG3350;

d) optionally from 0.01% to 0.5% w/w of BHT; and

e) optionally from 0.5% to 10% w/w of polyvinyl caprolactam-polyvinylacetate-polyethylene glycol graft copolymer.

In one embodiment, the pharmaceutical composition of the inventioncomprises:

a) from 5% to 15% w/w of compound of Formula (I);

b) from 70% to 90% w/w of lauroyl polyoxyl-32 glycerides;

c) from 10% to 25% w/w of PEG3350;

d) optionally from 0.01% to 0.5% w/w of BHT; and

e) optionally from 0.5% to 10% w/w of polyvinyl pyrrolidone polyvinylacetate copolymer.

In one embodiment, the pharmaceutical composition of the inventioncomprises:

a) from 5% to 15% w/w of compound of Formula (I);

b) from 70% to 90% w/w of lauroyl polyoxyl-32 glycerides;

c) from 5% to 10% w/w of caprylic acid; and

d) optionally from 0.01% to 0.5% w/w of BHT.

In one embodiment, the pharmaceutical composition of the inventioncomprises:

a) from 5% to 15% w/w of compound of Formula (I);

b) from 70% to 90% w/w of lauroyl polyoxyl-32 glycerides;

c) from 5% to 10% w/w of caprylic acid;

d) optionally from 0.01% to 0.5% w/w of BHT;

e) optionally from 0.5% to 10% w/w of SL S; and

f) optionally from 0.5% to 10% w/w of hydroxypropylmethylcellulose.

In one embodiment, the pharmaceutical composition of the inventioncomprises:

a) from 5% to 15% w/w of compound of Formula (I);

b) from 70% to 90% w/w of lauroyl polyoxyl-32 glycerides;

c) from 5% to 10% w/w of caprylic acid;

d) optionally from 0.01% to 0.5% w/w of BHT; and

f) optionally from 0.5% to 10% w/w of hydroxypropylmethylcellulose.

In one embodiment, the pharmaceutical composition of the inventioncomprises:

a) from 5% to 15% w/w of compound of Formula (I);

b) from 70% to 90% w/w of lauroyl polyoxyl-32 glycerides;

c) from 5% to 10% w/w of caprylic acid;

d) optionally from 0.01% to 0.5% w/w of BHT; and

e) optionally from 0.5% to 10% w/w of poloxamer 407.

In one embodiment, the pharmaceutical composition of the inventioncomprises:

a) from 5% to 15% w/w of compound of Formula (I);

b) from 70% to 90% w/w of lauroyl polyoxyl-32 glycerides;

c) from 5% to 10% w/w of caprylic acid;

d) optionally from 0.01% to 0.5% w/w of BHT; and

e) optionally from 0.5% to 10% w/w of polyvinyl caprolactam-polyvinylacetate-polyethylene glycol graft copolymer.

In one embodiment, the pharmaceutical composition of the inventioncomprises:

a) from 5% to 15% w/w of compound of Formula (I);

b) from 70% to 90% w/w of lauroyl polyoxyl-32 glycerides;

c) from 5% to 10% w/w of caprylic acid;

d) optionally from 0.01% to 0.5% w/w of BHT; and

e) optionally from 0.5 to 10% w/w polyvinyl pyrrolidone polyvinylacetate copolymer

In one embodiment, the pharmaceutical composition of the inventioncomprises:

a) from 5% to 15% w/w of compound of Formula (I) in the form of a salt,preferably as the HCl salt or the esylate salt;

b) from 70% to 90% w/w of lauroyl polyoxyl-32 glycerides;

c) from 10% to 25% w/w of PEG400;

d) optionally from 0.01% to 0.5% w/w of BHT;

e) optionally from 0.5% to 10% w/w of SL S; and

f) optionally from 0.5% to 10% w/w of hydroxypropylmethylcellulose.

In one embodiment, the pharmaceutical composition of the inventioncomprises:

a) from 5% to 15% w/w of compound of Formula (I) in the form of a salt,preferably as the HCl salt or the esylate salt;

b) from 70% to 90% w/w of lauroyl polyoxyl-32 glycerides;

c) from 10% to 25% w/w of PEG400;

d) optionally from 0.01% to 0.5% w/w of BHT; and

f) optionally from 0.5% to 10% w/w of hydroxypropylmethylcellulose.

In one embodiment, the pharmaceutical composition of the inventioncomprises:

a) from 5% to 15% w/w of compound of Formula (I) in the form of a salt,preferably as the HCl salt or the esylate salt;

b) from 70% to 90% w/w of lauroyl polyoxyl-32 glycerides;

c) from 10% to 25% w/w of PEG400;

d) optionally from 0.01% to 0.5% w/w of BHT; and

e) optionally from 0.5% to 10% w/w of poloxamer 407.

In one embodiment, the pharmaceutical composition of the inventioncomprises:

a) from 5% to 15% w/w of compound of Formula (I) in the form of a salt,preferably as the HCl salt or the esylate salt;

b) from 70% to 90% w/w of lauroyl polyoxyl-32 glycerides;

c) from 10% to 25% w/w of PEG400;

d) optionally from 0.01% to 0.5% w/w of BHT; and

e) optionally from 0.5% to 10% w/w polyvinyl caprolactam-polyvinylacetate-polyethylene glycol graft copolymer.

In one embodiment, the pharmaceutical composition of the inventioncomprises:

a) from 5% to 15% w/w of compound of Formula (I) in the form of a salt,preferably as the HCl salt or the esylate salt;

b) from 70% to 90% w/w of lauroyl polyoxyl-32 glycerides;

c) from 10% to 25% w/w of PEG400;

d) optionally from 0.01% to 0.5% w/w of BHT; and

e) optionally from 0.5% to 10% w/w polyvinyl pyrrolidone polyvinylacetate copolymer.

In one embodiment, the pharmaceutical composition of the inventioncomprises:

a) from 5% to 15% w/w of compound of Formula (I) in the form of a salt,preferably as the HCl salt or the esylate salt;

b) from 70% to 90% w/w of lauroyl polyoxyl-32 glycerides;

c) from 10% to 25% w/w of PEG3350;

d) optionally from 0.01% to 0.5% w/w of BHT;

e) optionally from 0.5% to 10% w/w of SL S; and

f) optionally from 0.5% to 10% w/w of hydroxypropylmethylcellulose.

In one embodiment, the pharmaceutical composition of the inventioncomprises:

a) from 5% to 15% w/w of compound of Formula (I) in the form of a salt,preferably as the HCl salt or the esylate salt;

b) from 70% to 90% w/w of lauroyl polyoxyl-32 glycerides;

c) from 10% to 25% w/w of PEG3350;

d) optionally from 0.01% to 0.5% w/w of BHT; and

f) optionally from 0.5% to 10% w/w of hydroxypropylmethylcellulose.

In one embodiment, the pharmaceutical composition of the inventioncomprises:

a) from 5% to 15% w/w of compound of Formula (I) in the form of a salt,preferably as the HCl salt or the esylate salt;

b) from 70% to 90% w/w of lauroyl polyoxyl-32 glycerides;

c) from 10% to 25% w/w of PEG3350;

d) optionally from 0.01% to 0.5% w/w of BHT; and

e) optionally from 0.5% to 10% w/w of poloxamer 407.

In one embodiment, the pharmaceutical composition of the inventioncomprises:

a) from 5% to 15% w/w of compound of Formula (I) in the form of a salt,preferably as the HCl salt or the esylate salt;

b) from 70% to 90% w/w of lauroyl polyoxyl-32 glycerides;

c) from 10% to 25% w/w of PEG3350;

d) optionally from 0.01% to 0.5% w/w of BHT; and

e) optionally from 0.5% to 10% w/w of polyvinyl caprolactam-polyvinylacetate-polyethylene glycol graft copolymer.

In one embodiment, the pharmaceutical composition of the inventioncomprises:

a) from 5% to 15% w/w of compound of Formula (I) in the form of a salt,preferably as the HCl salt or the esylate salt;

b) from 70% to 90% w/w of lauroyl polyoxyl-32 glycerides;

c) from 10% to 25% w/w of PEG3350;

d) optionally from 0.01% to 0.5% w/w of BHT; and

e) optionally from 0.5% to 10% w/w polyvinyl pyrrolidone polyvinylacetate copolymer.

In one embodiment, the pharmaceutical composition of the inventioncomprises:

a) from 5% to 15% w/w of compound of Formula (I) in the form of a salt,preferably as the HCl salt or the esylate salt;

b) from 70% to 90% w/w of lauroyl polyoxyl-32 glycerides;

c) from 5% to 10% w/w of caprylic acid;

d) optionally from 0.01% to 0.5% w/w of BHT;

e) optionally from 0.5% to 10% w/w of SL S; and

f) optionally from 0.5% to 10% w/w of hydroxypropylmethylcellulose.

In one embodiment, the pharmaceutical composition of the inventioncomprises:

a) from 5% to 15% w/w of compound of Formula (I) in the form of a salt,preferably as the HCl salt or the esylate salt;

b) from 70% to 90% w/w of lauroyl polyoxyl-32 glycerides;

c) from 5% to 10% w/w of caprylic acid;

d) optionally from 0.01% to 0.5% w/w of BHT; and

f) optionally from 0.5% to 10% w/w of hydroxypropylmethylcellulose.

In one embodiment, the pharmaceutical composition of the inventioncomprises:

a) from 5% to 15% w/w of compound of Formula (I) in the form of a salt,preferably as the HCl salt or the esylate salt;

b) from 70% to 90% w/w of lauroyl polyoxyl-32 glycerides;

c) from 5% to 10% w/w of caprylic acid;

d) optionally from 0.01% to 0.5% w/w of BHT; and

e) optionally from 0.5% to 10% w/w of poloxamer 407.

In one embodiment, the pharmaceutical composition of the inventioncomprises:

a) from 5% to 15% w/w of compound of Formula (I) in the form of a salt,preferably as the HCl salt or the esylate salt;

b) from 70% to 90% w/w of lauroyl polyoxyl-32 glycerides;

c) from 5% to 10% w/w of caprylic acid;

d) optionally from 0.01% to 0.5% w/w of BHT; and

e) optionally from 0.5% to 10% w/w of polyvinyl caprolactam-polyvinylacetate-polyethylene glycol graft copolymer.

In one embodiment, the pharmaceutical composition of the inventioncomprises:

a) from 5% to 15% w/w of compound of Formula (I) in the form of a salt,preferably as the HCl salt or the esylate salt;

b) from 70% to 90% w/w of lauroyl polyoxyl-32 glycerides;

c) from 5% to 10% w/w of caprylic acid;

d) optionally from 0.01% to 0.5% w/w of BHT; and

e) optionally from 0.5% to 10% w/w polyvinyl pyrrolidone polyvinylacetate copolymer

In one embodiment, the pharmaceutical composition of the inventioncomprises:

a) from 5% to 15% w/w of compound of Formula (I) in the form of a salt,preferably as the HCl salt or the esylate salt;

b) from 70% to 90% w/w of Vitamin E TPGS;

c) from 10% to 25% w/w of PEG400;

d) optionally from 0.01% to 0.5% w/w of BHT;

e) optionally from 0.5% to 10% w/w of SL S; and

f) optionally from 0.5% to 10% w/w of hydroxypropylmethylcellulose.

In one embodiment, the pharmaceutical composition of the inventioncomprises:

a) from 5% to 15% w/w of compound of Formula (I) in the form of a salt,preferably as the HCl salt or the esylate salt;

b) from 70% to 90% w/w of Vitamin E TPGS;

c) from 10% to 25% w/w of PEG400;

d) optionally from 0.01% to 0.5% w/w of BHT; and

f) optionally from 0.5% to 10% w/w of hydroxypropylmethylcellulose.

In one embodiment, the pharmaceutical composition of the inventioncomprises:

a) from 5% to 15% w/w of compound of Formula (I) in the form of a salt,preferably as the HCl salt or the esylate salt;

b) from 70% to 90% w/w of Vitamin E TPGS;

c) from 10% to 25% w/w of PEG400;

d) optionally from 0.01% to 0.5% w/w of BHT; and

e) optionally from 0.5% to 10% w/w of poloxamer 407

In one embodiment, the pharmaceutical composition of the inventioncomprises:

a) from 5% to 15% w/w of compound of Formula (I) in the form of a salt,preferably as the HCl salt or the esylate salt;

b) from 70% to 90% w/w of Vitamin E TPGS;

c) from 10% to 25% w/w of PEG400;

d) optionally from 0.01% to 0.5% w/w of BHT; and

e) optionally from 0.5% to 10% w/w polyvinyl caprolactam-polyvinylacetate-polyethylene glycol graft copolymer

In one embodiment, the pharmaceutical composition of the inventioncomprises:

a) from 5% to 15% w/w of compound of Formula (I) in the form of a salt,preferably as the HCl salt or the esylate salt;

b) from 70% to 90% w/w of Vitamin E TPGS;

c) from 10% to 25% w/w of PEG400;

d) optionally from 0.01% to 0.5% w/w of BHT; and

e) optionally from 0.5% to 10% w/w polyvinyl pyrrolidone polyvinylacetate copolymer In one embodiment, the pharmaceutical composition ofthe invention comprises:

a) from 5% to 15% w/w of compound of Formula (I) in the form of a salt,preferably as the HCl salt or the esylate salt;

b) from 70% to 90% w/w of Vitamin E TPGS;

c) from 10% to 25% w/w of PEG3350;

d) optionally from 0.01% to 0.5% w/w of BHT;

e) optionally from 0.5% to 10% w/w of SL S; and

f) optionally from 0.5% to 10% w/w of hydroxypropylmethylcellulose.

In one embodiment, the pharmaceutical composition of the inventioncomprises:

a) from 5% to 15% w/w of compound of Formula (I) in the form of a salt,preferably as the HCl salt or the esylate salt;

b) from 70% to 90% w/w of Vitamin E TPGS;

c) from 10% to 25% w/w of PEG3350;

d) optionally from 0.01% to 0.5% w/w of BHT; and

f) optionally from 0.5% to 10% w/w of hydroxypropylmethylcellulose.

In one embodiment, the pharmaceutical composition of the inventioncomprises:

a) from 5% to 15% w/w of compound of Formula (I) in the form of a salt,preferably as the HCl salt or the esylate salt;

b) from 70% to 90% w/w of Vitamin E TPGS;

c) from 10% to 25% w/w of PEG3350;

d) optionally from 0.01% to 0.5% w/w of BHT; and

e) optionally from 0.5% to 10% w/w of poloxamer 407.

In one embodiment, the pharmaceutical composition of the inventioncomprises:

a) from 5% to 15% w/w of compound of Formula (I) in the form of a salt,preferably as the HCl salt or the esylate salt;

b) from 70% to 90% w/w of Vitamin E TPGS;

c) from 10% to 25% w/w of PEG3350;

d) optionally from 0.01% to 0.5% w/w of BHT; and

e) optionally from 0.5% to 10% w/w of polyvinyl caprolactam-polyvinylacetate-polyethylene glycol graft copolymer.

In one embodiment, the pharmaceutical composition of the inventioncomprises:

a) from 5% to 15% w/w of compound of Formula (I) in the form of a salt,preferably as the HCl salt or the esylate salt;

b) from 70% to 90% w/w of Vitamin E TPGS;

c) from 10% to 25% w/w of PEG3350;

d) optionally from 0.01% to 0.5% w/w of BHT; and

e) optionally from 0.5% to 10% w/w polyvinyl pyrrolidone polyvinylacetate copolymer.

In one embodiment, the pharmaceutical composition of the inventioncomprises:

a) from 5% to 15% w/w of compound of Formula (I) in the form of a salt,preferably as the HCl salt or the esylate salt;

b) from 70% to 90% w/w of Vitamin E TPGS;

c) from 5% to 10% w/w of caprylic acid;

d) optionally from 0.01% to 0.5% w/w of BHT;

e) optionally from 0.5% to 10% w/w of SL S; and

f) optionally from 0.5% to 10% w/w of hydroxypropylmethylcellulose.

In one embodiment, the pharmaceutical composition of the inventioncomprises:

a) from 5% to 15% w/w of compound of Formula (I) in the form of a salt,preferably as the HCl salt or the esylate salt;

b) from 70% to 90% w/w of Vitamin E TPGS;

c) from 5% to 10% w/w of caprylic acid;

d) optionally from 0.01% to 0.5% w/w of BHT; and

f) optionally from 0.5% to 10% w/w of hydroxypropylmethylcellulose.

In one embodiment, the pharmaceutical composition of the inventioncomprises:

a) from 5% to 15% w/w of compound of Formula (I) in the form of a salt,preferably as the HCl salt or the esylate salt;

b) from 70% to 90% w/w of Vitamin E TPGS;

c) from 5% to 10% w/w of caprylic acid;

d) optionally from 0.01% to 0.5% w/w of BHT; and

e) optionally from 0.5% to 10% w/w of poloxamer 407.

In one embodiment, the pharmaceutical composition of the inventioncomprises:

a) from 5% to 15% w/w of compound of Formula (I) in the form of a salt,preferably as the HCl salt or the esylate salt;

b) from 70% to 90% w/w of Vitamin E TPGS;

c) from 5% to 10% w/w of caprylic acid;

d) optionally from 0.01% to 0.5% w/w of BHT; and

e) optionally from 0.5% to 10% w/w of polyvinyl caprolactam-polyvinylacetate-polyethylene glycol graft copolymer

In one embodiment, the pharmaceutical composition of the inventioncomprises:

a) from 5% to 15% w/w of compound of Formula (I) in the form of a salt,preferably as the HCl salt or the esylate salt;

b) from 70% to 90% w/w of Vitamin E TPGS;

c) from 5% to 10% w/w of caprylic acid;

d) optionally from 0.01% to 0.5% w/w of BHT; and

e) optionally from 0.5% to 10% w/w polyvinyl pyrrolidone polyvinylacetate copolymer

Dosage Form

In one embodiment, the pharmaceutical composition of the invention is ina form suitable for oral administration. Such suitable administrationform may be solid, semi-solid or liquid. Such suitable administrationform will be clear to the skilled person; reference is made to thelatest edition of Remington's Pharmaceutical Sciences.

Some preferred, but non-limiting examples of such forms include capsules(including soft and hard gelatin capsules), tablets, pills, powders,lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutionsand syrups.

The pharmaceutical composition of the invention is preferably in a unitdosage form, and may be suitably packaged, for example in a box,blister, vial, bottle, sachet, ampoule or in any other suitablesingle-dose or multi-dose holder or container (which may be properlylabeled); optionally with one or more leaflets containing productinformation and/or instructions for use. Such a unit dosage form cancontain for example about 5 mg to about 200 mg of the pharmaceuticallyactive ingredient, preferably about 10 mg to about 100 mg.

The pharmaceutical composition of the invention may also be formulatedso as to provide rapid, sustained or delayed release of the activecompound(s) contained therein.

Manufacturing of the Pharmaceutical Composition

The pharmaceutical composition of the invention may be manufactured bymethods well known by one skilled in the art.

In one embodiment, the pharmaceutical composition of the invention isunder solid or semi-solid form. Solid dispersion may be preparedconventionally using methods such as for example fusion (melt), meltgranulation, solvent evaporation, spray drying, lyophilization (freezedrying), hotmeltextrusion, electrostatic spinning method, coating onsugar beads using fluidized bed coating system or supercritical fluidtechnology.

In one embodiment, the pharmaceutical composition of the invention isunder the form of capsules, preferably hard gelatin capsules. In suchcase, the capsules may be manufactured from a common blend usingconventional mixing and capsule filling processes according to GoodManufacturing Practice.

In one embodiment, the manufacturing process of the capsules comprisesthe following steps:

-   -   i) lauroyl polyoxyl-32 glycerides is melted at a temperature not        less than 50° C. but not exceeding 80° C.;    -   ii) optionally, further excipients, such as for example caprylic        acid, sodium lauryl sulphate, hydroxypropylmethylcellulose, PEG,        polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol        graft copolymer, polyvinyl pyrrolidone polyvinyl acetate        copolymer, poloxomer 407 and/or BHT, are then added to the        lauroyl polyoxyl-32 glycerides and mixed together using a        suitable mixer;    -   iii) the compound of Formula (I) as either the free base or        suitable salt form, preferably the HCl salt or esylate salt, is        then added gradually under continuous mixing using a suitable        mixer to produce a visually uniform distribution of the drug        substance with no observable lumps or agglomerates;    -   iv) mixing is then continued for at least 30 minutes to ensure        that the drug substance is homogeneously distributed as        determined visually;    -   v) the blend is then maintained in the molten state with        continued mixing and is filled into appropriately sized gelatin        capsule shells to the target capsule fill weight.

As already mention above, the gelatin capsule shells may optionallycomprise additional components such as for example polyethylene glycoland sodium lauryl sulphate.

Capsule filling is undertaken using conventional capsule filling methodsand equipment suitable for use with molten semi-solid formulations.

In another embodiment, the manufacturing process of the capsulescomprises the following steps:

-   -   i) Vitamin E TPGS is melted at a temperature not less than        50° C. but not exceeding 80° C.;    -   ii) optionally, further excipients, such as for example caprylic        acid, sodium lauryl sulphate, hydroxypropylmethylcellulose, PEG,        polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol        graft copolymer, polyvinyl pyrrolidone polyvinyl acetate        copolymer, poloxomer 407 and/or BHT, are then added to the        lauroyl polyoxyl-32 glycerides and mixed together using a        suitable mixer;    -   iii) the compound of Formula (I) as either the free base or        suitable salt form, preferably the HCl salt or esylate salt, is        then added gradually under continuous mixing using a suitable        mixer to produce a visually uniform distribution of the drug        substance with no observable lumps or agglomerates;    -   iv) mixing is then continued for at least 30 minutes to ensure        that the drug substance is homogeneously distributed as        determined visually;    -   v) the blend is then maintained in the molten state with        continued mixing and is filled into appropriately sized gelatin        capsule shells to the target capsule fill weight.

Dose

Depending on the condition to be prevented or treated and the form ofadministration, the pharmaceutical composition of the invention may beadministered as a single daily dose, divided over one or more dailydoses.

In one embodiments, the pharmaceutical composition of the invention isadministered in a dose such that it corresponds administering about 5 mgto about 200 mg of the pharmaceutically active ingredient (free baseequivalent) to the subject per administration, preferably about 10 mg toabout 100 mg.

In one embodiments, an effective dose of the pharmaceutically activeingredient can range from about 0.08 to about 3.3 mg/kg, preferablyabout 0.15 to about 1.7 mg/kg

Uses

Another object of this invention is a medicament comprising thepharmaceutical composition of the invention.

The invention is further directed to the use of the pharmaceuticalcomposition of the invention to inhibit A2A receptor.

According to a further feature of the present invention there isprovided a method for modulating A2A activity, in a patient, preferablya warm-blooded animal, and even more preferably a human, in need of suchtreatment, which comprises administering to said patient an effectiveamount of the pharmaceutical composition of the invention.

According to a further feature of the present invention there isprovided the use of the pharmaceutical composition of the invention forthe manufacture of a medicament for modulating A2A activity in apatient, in need of such treatment, which comprises administering tosaid patient an effective amount of the pharmaceutical composition ofthe invention.

In one embodiment, the invention relates to the use of thepharmaceutical composition of the invention, for increasing immunerecognition and destruction of the cancer cells.

The pharmaceutical composition of the invention is therefore useful forthe prevention and/or treatment of cancer, especially useful for thetreatment of cancer.

The invention further relates to a method for treatment of cancer, whichcomprises administering to a mammalian species in need thereof atherapeutically effective amount of the pharmaceutical composition ofthe invention.

The invention further provides the use of the pharmaceutical compositionof the invention for the manufacture of a medicament for treating and/orpreventing cancer.

The invention also provides for a method for delaying in patient theonset of cancer comprising the administration of a pharmaceuticallyeffective amount of the pharmaceutical composition of the invention to apatient in need thereof.

Preferably, the patient is a warm-blooded animal, more preferably ahuman.

Various cancers are known in the art. The cancer may be metastatic ornon-metastatic. The cancer may be familial or sporadic. In someembodiments, the cancer is selected from the group consisting of:leukemia and multiple myeloma. Additional cancers that can be treatedusing the methods of the invention include, for example, benign andmalignant solid tumors and benign and malignant non-solid tumors. In aspecific embodiment, the cancer is selected from breast, carcinoid,cervical, colorectal, endometrial, glioma, head and neck, liver, lung,melanoma, ovarian, pancreatic, prostate, renal, gastric, thyroid andurothelial cancers. In a specific embodiment, the cancer is breastcancer. In a specific embodiment, the cancer is carcinoid cancer. In aspecific embodiment, the cancer is cervical cancer. In a specificembodiment, the cancer is colorectal cancer. In a specific embodiment,the cancer is endometrial cancer. In a specific embodiment, the canceris glioma. In a specific embodiment, the cancer is head and neck cancer.In a specific embodiment, the cancer is liver cancer. In a specificembodiment, the cancer is lung cancer. In a specific embodiment, thecancer is melanoma. In a specific embodiment, the cancer is ovariancancer. In a specific embodiment, the cancer is pancreatic cancer. In aspecific embodiment, the cancer is prostate cancer. In a specificembodiment, the cancer is renal cancer. In a specific embodiment, thecancer is gastric cancer. In a specific embodiment, the cancer isthyroid cancer. In a specific embodiment, the cancer is urothelialcancer.

Examples of solid tumors include, but are not limited to: biliary tractcancer, brain cancer (including glioblastomas and medulloblastomas),breast cancer, carcinoid, cervical cancer, choriocarcinoma, coloncancer, colorectal cancer, endometrial cancer, esophageal cancer,gastric cancer, glioma, head and neck cancer, intraepithelial neoplasms(including Bowen's disease and Paget's disease), liver cancer, lungcancer, neuroblastomas, oral cancer (including squamous cell carcinoma),ovarian cancer (including those arising from epithelial cells, stromalcells, germ cells and mesenchymal cells), pancreatic cancer, prostatecancer, rectal cancer, renal cancer (including adenocarcinoma and Wilmstumor), sarcomas (including leiomyosarcoma, rhabdomyosarcoma,liposarcoma, fibrosarcoma and osteosarcoma), skin cancer (includingmelanoma, Kaposi's sarcoma, basocellular cancer and squamous cellcancer), testicular cancer including germinal tumors (seminomas, andnon-seminomas such as teratomas and choriocarcinomas), stromal tumors,germ cell tumors, thyroid cancer (including thyroid adenocarcinoma andmedullary carcinoma) and urothelial cancer.

Examples of solid tumors include, but are not limited to: biliary tractcancer, brain cancer (including glioblastomas and medulloblastomas),breast cancer, cervical cancer, choriocarcinoma, colon cancer,endometrial cancer, esophageal cancer, gastric cancer, intraepithelialneoplasms (including Bowen's disease and Paget's disease), liver cancer,lung cancer, neuroblastomas, oral cancer (including squamous cellcarcinoma), ovarian cancer (including those arising from epithelialcells, stromal cells, germ cells and mesenchymal cells), pancreaticcancer, prostate cancer, rectal cancer, renal cancer (includingadenocarcinoma and Wilms tumor), sarcomas (including leiomyosarcoma,rhabdomyosarcoma, liposarcoma, fibrosarcoma and osteosarcoma), skincancer (including melanoma, Kaposi's sarcoma, basocellular cancer andsquamous cell cancer), testicular cancer including germinal tumors(seminomas, and non-seminomas such as teratomas and choriocarcinomas),stromal tumors, germ cell tumors, and thyroid cancer (including thyroidadenocarcinoma and medullary carcinoma).

Examples of non-solid tumors include but are not limited tohematological neoplasms. As used herein, a hematologic neoplasm is aterm of art which includes lymphoid disorders, myeloid disorders, andAIDS associated leukemias.

Lymphoid disorders include but are not limited to acute lymphocyticleukemia and chronic lymphoproliferative disorders (e.g., lymphomas,myelomas, and chronic lymphoid leukemias). Lymphomas include, forexample, Hodgkin's disease, non-Hodgkin's lymphoma lymphomas, andlymphocytic lymphomas). Chronic lymphoid leukemias include, for example,T cell chronic lymphoid leukemias and B cell chronic lymphoid leukemias.

The invention further relates to the use of the pharmaceuticalcomposition of the invention for the prevention and/or treatment ofradiation-induced fibrosis, connective tissue diseases (such as forexample Sjogrën syndrome, i.e. scleroderma), chronic bacterial infection(such as for example Helicobacter pylori), abnormal scarring (keloids)and polymicrobial sepsis.

The invention further relates to a method for treatment or prevention ofradiation-induced fibrosis, connective tissue diseases (such as forexample Sjogrën syndrome, i.e. scleroderma), chronic bacterial infection(such as for example Helicobacter pylori), abnormal scarring (keloids)and polymicrobial sepsis, which comprises administering to a mammalianspecies in need thereof a therapeutically effective amount of thepharmaceutical composition of the invention.

The invention further provides the use of the pharmaceutical compositionof the invention for the manufacture of a medicament for treating and/orpreventing radiation-induced fibrosis, connective tissue diseases (suchas for example Sjogrën syndrome, i.e. scleroderma), chronic bacterialinfection (such as for example Helicobacter pylori), abnormal scarring(keloids) and polymicrobial sepsis.

The invention also provides for a method for delaying in patient theonset of radiation-induced fibrosis, connective tissue diseases (such asfor example Sjogrën syndrome, i.e. scleroderma), chronic bacterialinfection (such as for example Helicobacter pylori), abnormal scarring(keloids) and polymicrobial sepsis, comprising the administration of apharmaceutically effective amount of the pharmaceutical composition ofthe invention to a patient in need thereof.

Combination

The invention also relates to a combination comprising:

-   -   (a) at least one A2A adenosine receptor (A2AR) inhibitor, and    -   (b) at least one anticancer agent.

In a preferred embodiment, the invention provides a combinationcomprising:

-   -   (a) at least one A2AR inhibitor being a thiocarbamate        derivative, more preferably a thiocarbamate derivative of        Formula (I)

-   -   -   or a pharmaceutically acceptable salt or solvate thereof,            wherein R¹ and R² are as defined above; and

    -   (b) at least one anticancer agent.

As detailed below, the anticancer agent may be selected fromimmunotherapeutic agents, chemotherapeutic agents, antiangiogenicagents, multidrug resistance-associated proteins inhibitors,radiotherapeutic agents, and any combination thereof.

In the context of the present invention the term “combination”preferably means a combined occurrence of an A2AR inhibitor and of ananticancer agent. Therefore, the combination of the invention may occureither as one composition, comprising all the components in one and thesame mixture (e.g. a pharmaceutical composition), or may occur as a kitof parts, wherein the different components form different parts of sucha kit of parts. The administration of the A2AR inhibitor and of theanticancer agent may occur either simultaneously or timely staggered,with similar or different timing of administration (i.e. similar ordifferent numbers of administration of each component), either at thesame site of administration or at different sites of administration,under similar of different dosage forms.

The invention is based on the surprising finding that the combination ofan A2AR inhibitor and an anticancer agent (such as for example animmunotherapeutic agent, especially a checkpoint inhibitor), shows anextremely advantageous inhibition of tumor growth and/or reduction inthe number of cancer cells, resulting in enhanced survival which couldnot be expected from the prior art. Thus, the combined treatment with anA2AR inhibitor and with an anticancer agent, could strongly decrease theharmful impact of a disease to be treated, e.g. the growth rate of atumor. These effects are illustrated in the Examples hereinafter.

A2AR Inhibitor

As a first component, the combination of the invention includes an A2ARinhibitor. Preferably, the A2AR inhibitor is a thiocarbamate derivative,especially a thiocarbamate derivative as those disclosed inPCT/EP2018/058301. More preferably the A2AR inhibitor is a thiocarbamatederivative of formula (I) as described above.

In a preferred embodiment, the combination of the invention thuscomprises as A2AR inhibitor a compound of Formula (I):

-   -   or a pharmaceutically acceptable salt or solvate thereof,        wherein R¹ and R² are as defined above.

All the embodiment relative to the A2AR inhibitor detailed above applyto the combination of the invention.

Anticancer Agent

As a second component, the combination of the invention includes atleast one anticancer agent.

In one embodiment, the anticancer agent is selected fromimmunotherapeutic agents, chemotherapeutic agents, antiangiogenicagents, multidrug resistance-associated proteins inhibitors,radiotherapeutic agents, and any combination thereof.

In one embodiment, the combination of the invention comprises a singleanticancer agent. In another embodiment, the combination of theinvention comprises a plurality of anticancer agents; preferably two,three or four anticancer agents as defined below. In case of use of acombination of anticancer agents in the combination of the invention,the anticancer agents may be of the same class of agents or of differentclasses of agents. For example, a combination of an immunotherapeuticagent and of a chemotherapeutic agent may be used with the A2ARinhibitor.

Immunotherapeutic Agent

In one embodiment, the combination of the invention includes animmunotherapeutic agent as anticancer agent.

In such case the invention relates to a combination comprising:

-   -   (a) at least one A2A adenosine receptor (A2AR) inhibitor, and    -   (b) at least one immunotherapeutic agent.

In a preferred embodiment, the invention provides a combinationcomprising:

-   -   (a) at least one A2AR inhibitor being a thiocarbamate        derivative, more preferably a thiocarbamate derivative of        Formula (I) or a pharmaceutically acceptable salt or solvate        thereof, wherein R¹ and R² are as defined above; and    -   (b) at least one immunotherapeutic agent.

In the present invention, “immunotherapy” refers to a therapy aiming atinducing and/or enhancing an immune response towards a specific target,for example towards cancer cells. In such last case, it is referred toas cancer immunotherapy.

The immunotherapeutic agent is for example selected from checkpointinhibitors, checkpoint agonists (also called T-cell agonists), IDOinhibitors, PI3K inhibitors, adenosine receptor inhibitors,adenosine-producing enzymes inhibitors, CD40 agonists, IL2 variants,immune cells (for conducting adoptive transfer), therapeutic vaccines,and combinations thereof. In a specific embodiment, theimmunotherapeutic agent is a checkpoint inhibitor.

In one embodiment, the immunotherapeutic agent to be combined with theA2AR inhibitor of Formula (I) as described hereinabove comprises orconsists of checkpoint inhibitors, checkpoint agonists, IDO inhibitors,PI3K inhibitors, adenosine receptor inhibitors, adenosine-producingenzymes inhibitors, CD40 agonists, IL2 variants, immune cells (forconducting adoptive transfer), therapeutic vaccines, or any mixesthereof.

In the context of the present invention the term “combination”preferably means a combined occurrence of an A2AR inhibitor and of animmunotherapeutic agent. Therefore, the combination of the invention mayoccur either as one composition, comprising all the components in oneand the same mixture (e.g. a pharmaceutical composition), or may occuras a kit of parts, wherein the different components form different partsof such a kit of parts. The administration of the A2AR inhibitor and ofthe immunotherapeutic agent may occur either simultaneously or timelystaggered, with similar or different timing of administration (i.e.similar or different numbers of administration of each component),either at the same site of administration or at different sites ofadministration, under similar of different dosage forms. Suchcombination may induce an active immune response and thereby preventse.g. tumor growth or induces tumor regression.

Checkpoint Inhibitors

In one embodiment, the combination of the invention includes at leastone checkpoint inhibitor as immunotherapeutic agent.

Checkpoint inhibitors (CPI), that may also be referred to as immunecheckpoint inhibitors (ICI), block the interactions between inhibitoryreceptors expressed on T cells and their ligands. As a cancer treatment,the use of checkpoint inhibitor aims at preventing the activation ofinhibitory receptors expressed on T cells by ligands expressed by thetumor cells. The use of checkpoint inhibitors thus aims at preventingthe inhibition of T cells present in the tumor, i.e., tumor infiltratingT cells, and thus at enhancing the subject immune response towards thetumor cells.

Thus, the combination of the invention can restore immune functions intumor environments by using as a first component an A2AR inhibitor, andto antagonize checkpoint pathway signaling by preferably inhibiting orsuppressing signal transduction by using as second component acheckpoint inhibitor as immunotherapeutic agent.

Examples of checkpoint inhibitors include, without being limited to:

-   -   inhibitors of the cell surface receptor PD-1 (programmed cell        death protein 1), also known as CD279 (cluster differentiation        279);    -   inhibitors of the ligand PD-L1 (programmed death-ligand 1), also        known as CD274 (cluster of differentiation 274) or B7-H1 (B7        homolog 1);    -   inhibitors of the cell surface receptor CTLA4 or CTLA-4        (cytotoxic T-lymphocyte-associated protein 4), also known as        CD152 (cluster of differentiation 152);    -   inhibitors of LAG-3 (lymphocyte-activation gene 3), also known        as CD223 (cluster differentiation 223);    -   inhibitors of TIM-3 (T-cell immunoglobulin and mucin-domain        containing-3), also known as HAVCR2 (hepatitis A virus cellular        receptor 2) or CD366 (cluster differentiation 366);    -   inhibitors of TIGIT (T cell immunoreceptor with Ig and ITIM        domains), also known as VSIG9 (V-Set And Immunoglobulin        Domain-Containing Protein 9) or VSTM3 (V-Set And Transmembrane        Domain-Containing Protein 3);    -   inhibitors of BTLA (B and T lymphocyte attenuator), also known        as CD272 (cluster differentiation 272);    -   inhibitors of CEACAM-1 (carcinoembryonic antigen-related cell        adhesion molecule 1) also known as CD66a (cluster        differentiation 66a); and    -   inhibitors of GITR (glucocorticoid-induced TNFR-related protein)        also known as TNFRSF18 (tumor necrosis factor receptor        superfamily member 18) or AITR (activation-inducible TNFR family        receptor).

In one embodiment, the checkpoint inhibitor is selected from the groupcomprising or consisting of inhibitors of PD-1, inhibitors of PD-L1,inhibitors of CTLA4, inhibitors of LAG-3, inhibitors of TIM-3,inhibitors of TIGIT, inhibitors of BTLA, inhibitors of CEACAM-1,inhibitors of GITR and any mixtures thereof.

In one embodiment, the checkpoint inhibitor is selected from the groupcomprising or consisting of inhibitors of PD-1, inhibitors of PD-L1,inhibitors of CTLA-4, inhibitors of TIGIT and any mixtures thereof.

In one embodiment, the checkpoint inhibitor is selected from the groupcomprising or consisting of inhibitors of PD-1, inhibitors of PD-L1,inhibitors of CTLA-4 and any mixtures thereof.

In one embodiment, the checkpoint inhibitor is an inhibitor of PD-1,also referred to as an anti-PD-1. Inhibitors of PD-1 may includeantibodies targeting PD-1, in particular monoclonal antibodies, andnon-antibody inhibitors such as small molecule inhibitors.

Examples of inhibitors of PD-1 include, without being limited to,pembrolizumab, nivolumab, cemiplimab, tislelizumab, spartalizumab,ABBV-181, JNJ-63723283, BI 754091, MAG012, TSR-042, AGEN2034.Pembrolizumab is also known as MK-3475, MK03475, lambrolizumab, orSCH-900475. The trade name of pembrolizumab is Keytruda®. Nivolumab isalso known as ONO-4538, BMS-936558, MDX1106, or GTPL7335. The trade nameof nivolumab is Opdivo®. Cemiplimab is also known as REGN2810 orREGN-2810. Tislelizumab is also known as BGB-A317. Spartalizumab is alsoknown as PDR001 or PDR-001.

In one embodiment, the checkpoint inhibitor is selected from the groupcomprising or consisting of pembrolizumab, nivolumab, cemiplimab,tislelizumab, spartalizumab, ABBV-181, JNJ-63723283, BI 754091, MAG012,TSR-042, AGEN2034, and any mixtures thereof.

In one embodiment, the checkpoint inhibitor is an inhibitor of PD-L1,also referred to as an anti-PD-L1. Inhibitors of PD-L1 may includeantibodies targeting PD-L1, in particular monoclonal antibodies, andnon-antibody inhibitors such as small molecule inhibitors.

Examples of inhibitors of PD-L1 include, without being limited to,avelumab, atezolizumab, durvalumab and LY3300054. Avelumab is also knownas MSB0010718C, MSB-0010718C, MSB0010682, or MSB-0010682. The trade nameof avelumab is Bavencio®. Atezolizumab is also known as MPDL3280A (cloneYW243.55.S70), MPDL-3280A, RG-7446 or RG7446. The trade name ofatezolizumab is Tecentriq®. Durvalumab is also known as MEDI4736 orMEDI-4736. The trade name of durvalumab is Imfinzi®.

In one embodiment, the checkpoint inhibitor is selected from the groupcomprising or consisting of avelumab, atezolizumab, durvalumab,LY3300054, and any mixtures thereof.

In one embodiment, the checkpoint inhibitor is an inhibitor of CTLA-4,also referred to as an anti-CTLA-4.

Inhibitors of CTLA-4 may include antibodies targeting CTLA-4, inparticular monoclonal antibodies, and non-antibody inhibitors such assmall molecule inhibitors.

Examples of inhibitors of CTLA-4 include, without being limited to,ipilimumab and tremelimumab. Ipilimumab is also known as BMS-734016,MDX-010, or MDX-101. The trade name of ipilimumab is Yervoy®.Tremelimumab is also known as ticilimumab, CP-675, or CP-675,206.

In one embodiment, the at least one checkpoint inhibitor is selectedfrom the group comprising or consisting of ipilimumab, tremelimumab, andany mixtures thereof.

In one embodiment, the checkpoint inhibitor is an inhibitor of TIGIT,also referred to as an anti-TIGIT.

In one embodiment of various methods, pharmaceutical compositions, kits,or uses provided herein, the anti-human TIGIT monoclonal antibody orantigen binding fragment thereof is BMS-986207 (Bristol-Myers Squibb,New York, N.Y.).

In another embodiment of various methods, pharmaceutical compositions,kits, or uses provided herein, the anti-human TIGIT monoclonal antibodyor antigen binding fragment thereof is OMP-313M32 (OncoMedPharmaceuticals, Redwood city, CA).

In another embodiment of various methods, pharmaceutical compositions,kits, or uses provided herein, the anti-human TIGIT monoclonal antibodyor antigen binding fragment thereof MK-7684 (Merck & Co., Kenilworth,N.J.).

In yet another embodiment of various methods, pharmaceuticalcompositions, kits, or uses provided herein, the anti-human TIGITmonoclonal antibody or antigen binding fragment thereof is MTIG7192A(also known as RG6058, U.S. Publ. No. 2017/0088613).

In still another embodiment of various methods, pharmaceuticalcompositions, kits, or uses provided herein, the anti-human TIGITmonoclonal antibody or antigen binding fragment thereof is PTZ-201(Potenza Therapeutics, Cambridge, Mass.; also known as ASP8374, AstellasPharma, Tokyo, Japan).

In another embodiment of various methods, pharmaceutical compositions,kits, or uses provided herein, the anti-human TIGIT monoclonal antibodyor antigen binding fragment thereof COM902 (Compugen LTD, Holon, Ill.).

In yet another embodiment of various methods, pharmaceuticalcompositions, kits, or uses provided herein, the anti-human TIGITmonoclonal antibody or antigen binding fragment thereof is described inWO2018/160704 (Seattle Genetics, Seattle, Wash.).

In yet another embodiment of various methods, pharmaceuticalcompositions, kits, or uses provided herein, the anti-human TIGITmonoclonal antibody or antigen binding fragment thereof is described inWO2019/023504 (Iteos Therapeutics). In certain preferred embodiments,the anti-human TIGIT antibody or antigen binding fragment comprises acombination of HCDR1, HCDR2, HCDR3, LCDR1, LCDR2 and LCDR3, wherein:

-   -   HCDR1 comprises or consists of SEQ ID NO: 1 (YTFTSYYMH),    -   HCDR2 comprises or consists of SEQ ID NO: 2 (VIGPSGASTSYAQKFQG),    -   HCDR3 comprises or consists of SEQ ID NO: 3 (ARDHSDYWSGIMEV),    -   LCDR1 comprises or consists of SEQ ID NO: 4 (RASQSVRSSYLA),    -   LCDR2 comprises or consists of SEQ ID NO: 5 (GASSRAT), and    -   LCDR3 comprises or consists of SEQ ID NO: 6 (QQYFSPPWT).

Checkpoint Agonists (T-Cell Agonists)

In one embodiment, the combination of the invention includes at leastone checkpoint agonist (also referred to as T-cell agonist) asimmunotherapeutic agent.

T-cell agonists act by activating stimulatory receptors expressed onimmune cells, such as T cells. As used herein, the term “stimulatoryreceptors” refer to receptors that induce a stimulatory signal uponactivation, and thus lead to an enhancement of the immune response. As acancer treatment, T-cell agonist therapy aims at activating stimulatoryreceptors expressed on immune cells present in a tumor. In particular,T-cell agonist therapy aims at enhancing the activation of T cellspresent in a tumor, i.e., tumor infiltrating T cells, and thus atenhancing the subject immune response towards the tumor cells.

Examples of T-cell agonists include, without being limited to:

-   -   agonists of CD137 (cluster differentiation 137) also known as        4-1BB or TNFRS9 (tumor necrosis factor receptor superfamily,        member 9);    -   agonists of OX40 receptor also known as CD134 (cluster        differentiation 134) or TNFRSF4 (tumor necrosis factor receptor        superfamily, member 4).

In one embodiment, the checkpoint agonist is selected from the groupcomprising or consisting of agonists of CD137, agonists of OX40 and anymixtures thereof.

Examples of agonists of CD137 include, without being limited, utomilumaband urelumab.

IDO Inhibitors

In one embodiment, the combination of the invention includes at leastone inhibitor of indoleamine-2,3-dioxygenase (IDO) as immunotherapeuticagent.

Indoleamine 2,3-dioxygenase enzyme catalyzes the first and rate-limitingstep of L-tryptophan (Trp) catabolism. IDO is implicated in immunemodulation through its ability to limit T cell function and engagemechanisms of immune tolerance. IDO activity in tumor cells serves toimpair anti-tumor responses. Inhibiting IDO thus enables to restoretumor immune surveillance.

Examples of IDO inhibitors include beta-carboline (also known asnorharmane), rosmarinic acid, 1-methyl-L-tryptophan (also known asL-1-MT), epacadostat, navoximod or those disclosed in WO2015/173764, andmore preferably those of formula II, II′ or II″.

In a preferred embodiment, the IDO inhibitor is selected among thosedisclosed in WO2015/173764, and more preferably those of formula II, II′or II″.

PI3Kgamma Inhibitors

In one embodiment, the combination of the invention includes at leastone PI3K inhibitor as immunotherapeutic agent.

A phosphoinositide 3-kinase inhibitor (PI3K inhibitor) is a class ofmedical drug that functions by inhibiting one or more of thephosphoinositide 3-kinase enzymes, which are part of the PI3K/AKT/mTORpathway, an important signaling pathway for many cellular functions suchas growth control, metabolism and translation initiation. Many types ofcancers have activated PI3K pathway, which prohibit tumor cells fromcell death.

There are a number of different classes and isoforms of PI3Ks. Class 1PI3Ks have a catalytic subunit known as p110, with four types(isoforms)—p110 alpha, p110 beta, p110 gamma and p110 delta.

In a preferred embodiment, the PI3K inhibitor is a PI3K-gamma inhibitor.

Examples of PI3K inhibitors include wortmannin, LY294002,demethoxyviridon, hibiscone C, Idelalisib, Copanlisib, Duvelisib,Taselisib, Buparlisib, Alpelisib, Umbralisib, Dactolisib, Voxtalisib,IPI-549, RP6530, IC87114 and TG100-115.

Examples of PI3K-gamma inhibitors include Copanlisib, Duvelisib,IPI-549, RP6530, IC87114 and TG100-115.

Adenosine Receptor Inhibitor

In one embodiment, the combination of the invention includes at leastone further inhibitor of adenosine receptors as immunotherapeutic agent.

As mentioned in the introduction, the adenosine receptors are a class ofpurinergic G protein-coupled receptors with adenosine as endogenousligand. There are four known types of adenosine receptors in humans: A1,A2A, A2B and A3.

The combination of the invention comprises as first component aninhibitor of A2A receptor, of formula (I) as defined above. The secondcomponent of the combination may be a further inhibitor of an adenosinereceptor, especially an inhibitor of A1, A2A, A2B or A3 receptors.Preferably the second component of the combination of the invention isan inhibitor of A2B receptor or an inhibitor of A3 receptor.

Examples of inhibitors of A2B receptor include ATL-801, CVT-6883,MRS-1706, MRS-1754, OSIP-339,391, PSB-603, PSB-0788 and PSB-1115.

Examples of inhibitors of A3 receptor include KF-26777, MRS-545,MRS-1191, MRS-1220, MRS-1334, MRS-1523, MRS-3777, MRE-3005-F20,MRE-3008-F20, PSB-11, OT-7999, VUF-5574 and SSR161421.

Adenosine-Producing Enzymes Inhibitors In one embodiment, thecombination of the invention includes at least one adenosine-producingenzymes inhibitor as immunotherapeutic agent.

Ectonucleotidases are families of nucleotide metabolizing enzymes thatmetabolize nucleotides to nucleosides. Subfamilies of ectonucleotidasesinclude: CD39/NTPDases (ecto-nucleotide triphosphatediphosphohydrolases), nucleotide pyrophosphatase/phosphodiesterase(NPP)-type ecto-phosphodiesterases, alkaline phosphatases andecto-5′-nucleotidases/CD73.

Among other functions, ectonucleotidases generate extracellularadenosine, the first step involving the conversion of ATP/ADP to AMP,carried out by ENTPD1, also known as CD39. The second step involves theconversion of AMP to adenosine. It is carried out by NT5E, also known asCD73. Thus ectonucleotidases are adenosine-producing enzymes.

As mentioned in the introduction, high levels of extracellular adenosineplay a significant role in the evasion of antitumor immune response.Thus using inhibitors of adenosine-producing enzymes, by enabling toreduce extracellular adenosine levels is beneficial in cancer therapy.

Examples of adenosine-producing enzymes inhibitors include:

-   -   inhibitors of CD39, also known as ENTPD1 or Ecto-nucleoside        triphosphate diphosphohydrolases (EC 3.6.1.5, apyrase),    -   inhibitors of CD73, also known as 5′-nucleotidase (5′-NT) or        ecto-5′-nucleotidase or NT5E,    -   inhibitors of Ecto-nucleotide pyrophosphatase/PDEs (EC 3.6.1.9        and EC 3.1.4.1) and    -   inhibitors of alkaline phosphatases (APs; EC 3.1.3.1),    -   inhibitors of CD38, also known as cyclic ADP ribose hydrolase or        ADP-ribosyl cyclase/cyclic ADP-ribose (cADPR) hydrolase).

Examples of adenosine-producing enzymes inhibitors include IPH5201,A001485, SRF617, ARL67156, POM-1, IPH5301, A000830, A001190, A001421,SRF373/NZV930, Darutumumab. More precisely, examples of CD39 inhibitorsinclude IPH5201, A001485, SRF617, ARL67156 and POM-1; examples of CD73inhibitors include IPH5301, A000830, A001190, A001421 and SRF373/NZV930;and examples of CD38 inhibitors include Darutumumab.

CD40 Agonists

In one embodiment, the combination of the invention includes at leastone CD40 agonist as immunotherapeutic agent.

CD40 is a cell surface receptor member of the tumor necrosis factor(TNF) receptor superfamily. It mediates both indirect tumor cell killingthrough the activation of the immune system and direct tumor cellapoptosis. Similar to the endogenous CD40 ligand (CD40L or CD154), CD40agonists bind to CD40 on a variety of immune cell types. This triggersthe cellular proliferation and activation of antigen-presenting cells(APCs), and activates B-cells, and effector and memory T-cells. Thisresults in an enhanced immune response against tumor cells.

Examples of CD40 agonists include CD40 agonistic antibodies andrecombinant CD40 agonists (ie proteins, but not antibodies). Examples ofCD40 agonistic antibodies include selicrelumab (formely known asRO7009789 and CP-870,893), APX005M, JNJ-64457107 (formerly ADC-1013),SEA-CD40, ChiLob 7/4, CDX-1140H, dacetuzumab (SGN-40) and ABBV-428.Examples of recombinant CD40 agonists include MEDI5083 and HERA-CD40L.

IL2 Variants

In one embodiment, the combination of the invention includes at leastone IL2 variant as immunotherapeutic agent.

Interleulin-2 (IL-2) is a powerful immune growth factor that plays animportant role in sustaining T cell response. The potential of IL-2 inexpanding T cells without loss of functionality has led to its early usein cancer immunotherapy.

Examples of IL2 variants include recombinant, PEGylated and/or mutatedIL2 variants, such as for example aldesleukin, monomethoxy PEG IL2,NKTR-214, MDNA-109, RO6874281 and ALKS-4230.

Immune Cells—Adoptive Cell Transfer

According to one embodiment, the immunotherapeutic agent is immune cellsto be used in an adoptive transfer of cells, also referred to asadoptive cell therapy (both also referred to as ACT), particularly anadoptive transfer of T cells, also referred to as adoptive T celltherapy.

As used herein, an adoptive transfer of cells or adoptive cell therapyis defined as the transfer, for example as an infusion, of immune cellsto a subject. As a cancer treatment, the adoptive transfer of immunecells to a subject aims at enhancing the subject immune response towardsthe cancer cells.

In one embodiment, the immune cells are T cells, in particular effectorT cells. Examples of effector T cells include CD4⁺ T cells and CD8⁺ Tcells.

In one embodiment, the transferred T cells are cytotoxic cells. Examplesof cytotoxic T cells include CD8⁺ T cells and natural killer (NK) cells,in particular natural killer (NK) T cells.

In one embodiment, the transferred immune cells as described hereinaboveare antigen-specific cells. In one embodiment, the transferred immunecells as described hereinabove are antigen-specific immune cells,wherein said antigen is specifically and/or abundantly expressed bycancer cells. In one embodiment, the transferred immune cells asdescribed hereinabove are cancer-specific immune cells, in other wordsthe transferred immune cells as described hereinabove specificallyrecognize cancer cells through an antigen specifically and/or abundantlyexpressed by said cancer cells. In one embodiment, the transferredimmune cells as described hereinabove are cancer-specific effector Tcells. In one embodiment, the transferred immune cells as describedhereinabove are cancer-specific CD8⁺ effector T cells, in particularcancer-specific cytotoxic CD8⁺ T cells. In one embodiment, thetransferred immune cells as described hereinabove are cancer-specificcytotoxic cells. In one embodiment, the transferred immune cells asdescribed hereinabove are cancer-specific NK cells. In one embodiment,the transferred immune cells as described hereinabove are tumor-specificimmune cells, in other words the transferred immune cells as describedhereinabove specifically recognize tumor cells through an antigenspecifically and/or abundantly expressed by said tumor cells. In oneembodiment, the transferred immune cells as described hereinabove aretumor-specific effector T cells. In one embodiment, the transferredimmune cells as described hereinabove are tumor-specific CD8⁺ effector Tcells, in particular tumor-specific cytotoxic CD8⁺ T cells. In oneembodiment, the transferred immune cells as described hereinabove aretumor-specific cytotoxic cells. In one embodiment, the transferredimmune cells as described hereinabove are tumor-specific NK cells.

In one embodiment, the transferred immune cells as described hereinaboveare autologous immune cells, in particular autologous T cells. Inanother embodiment, the transferred immune cells as describedhereinabove are allogenic (or allogenous) immune cells, in particularallogenic NK cells.

Methods to isolate T cells from a subject, in particularantigen-specific T cells, e.g., tumor-specific T cells, are well-knownin the art (see for example Rosenberg & Restifo, 2015, Science 348,62-68; Prickett et al., 2016, Cancer Immunol Res 4, 669-678; or Hinrichs& Rosenberg, 2014, Immunol Rev 257, 56-71). Methods to expand T cells exvivo are well-known in the art (see for example Rosenberg & Restifo,2015, Science 348, 62-68; Prickett et al., 2016, Cancer Immunol Res 4,669-678; or Hinrichs & Rosenberg, 2014, Immunol Rev 257, 56-71).Protocols for infusion of T cells in a subject, including pre-infusionconditioning regimens, are well-known in the art (see for exampleRosenberg & Restifo, 2015, Science 348, 62-68; Prickett et al., 2016,Cancer Immunol Res 4, 669-678; or Hinrichs & Rosenberg, 2014, ImmunolRev 257, 56-71).

In one embodiment, the immune cells are CAR immune cells, in particulara CAR T cells, in the context respectively of CAR immune cell therapyand CAR T cell therapy.

As used herein, CAR immune cell therapy is an adoptive cell therapywherein the transferred cells are immune cells as described hereinabove,such as T cells or NK cells, genetically engineered to express achimeric antigen receptor (CAR). As a cancer treatment, the adoptivetransfer of CAR immune cells to a subject aims at enhancing the subjectimmune response towards the cancer cells.

CARs are synthetic receptors consisting of a targeting moiety that isassociated with one or more signaling domains in a single fusionmolecule or in several molecules. In general, the binding moiety of aCAR consists of an antigen-binding domain of a single-chain antibody(scFv), comprising the light and variable fragments of a monoclonalantibody joined by a flexible linker. Binding moieties based on receptoror ligand domains have also been used successfully. The signalingdomains for first generation CARs are usually derived from thecytoplasmic region of the CD3zeta or the Fc receptor gamma chains. Firstgeneration CARs have been shown to successfully redirect T cellcytotoxicity, however, they failed to provide prolonged expansion andanti-tumor activity in vivo. Thus, signaling domains from co-stimulatorymolecules including CD28, OX-40 (CD134), and 4-1BB (CD137) have beenadded alone (second generation) or in combination (third generation) toenhance survival and increase proliferation of CAR modified T cells.

Thus, in one embodiment, the transferred T cells as describedhereinabove are CAR T cells. The expression of a CAR allows the T cellsto be redirected against a selected antigen, such as an antigenexpressed at the surface of cancer cells. In one embodiment, thetransferred CAR T cells recognize a tumor-specific antigen.

In another embodiment, the transferred NK cells as described hereinaboveare CAR NK cells. The expression of a CAR allows the NK cells to beredirected against a selected antigen, such as an antigen expressed atthe surface of cancer cells. In one embodiment, the transferred CAR NKcells recognize a tumor-specific antigen.

In one embodiment, the CAR immune cells as described hereinabove areautologous CAR immune cells, in particular autologous CAR T cells. Inanother embodiment, the CAR immune cells as described hereinabove areallogenic (or allogenous) CAR immune cells, in particular allogenic CARNK cells.

Therapeutic vaccines According to one embodiment, the immunotherapeuticagent is a therapeutic vaccine (sometimes also referred to as atreatment vaccine).

As used herein, a therapeutic vaccine is defined as the administrationof at least one tumor-specific antigen (e.g., synthetic long peptides orSLP), or of the nucleic acid encoding said tumor-specific antigen; theadministration of recombinant viral vectors selectively entering and/orreplicating in tumor cells; the administration of tumor cells; and/orthe administration of immune cells (e.g., dendritic cells) engineered topresent tumor-specific antigens and trigger an immune response againstthese antigens.

As a cancer treatment, therapeutic vaccines aim at enhancing the subjectimmune response towards the tumor cells.

Examples of therapeutic vaccines aiming at enhancing the subject immuneresponse towards the tumor cells include, without being limited to,viral-vector based therapeutic vaccines such as adenoviruses (e.g.,oncolytic adenoviruses), vaccinia viruses (e.g., modified vacciniaAnkara (MVA)), alpha viruses (e.g., Semliki Forrest Virus (SFV)),measles virus, Herpes simplex virus (HSV), and coxsackievirus; syntheticlong peptide (SLP) vaccines; and dendritic cell vaccines.

Chemotherapeutic Agent

In one embodiment, the combination of the invention includes at leastone chemotherapeutic agent as anticancer agent.

The chemotherapeutic agent is for example selected from anticanceralkylating agents, anticancer antimetabolites, anticancer antibiotics,plant-derived anticancer agents, anticancer platinum coordinationcompounds, Parp inhibitors, anti-hormone-sensitive cancer agents and anycombination thereof.

In one embodiment, the chemotherapeutic agent to be combined with theA2AR inhibitor of Formula (I) as described hereinabove comprises orconsists of anticancer alkylating agents, anticancer antimetabolites,anticancer antibiotics, plant-derived anticancer agents, anticancerplatinum coordination compounds, Parp inhibitors, anti-hormone-sensitivecancer agents and any combination thereof.

Anticancer Alkylating Agent

In one embodiment, the combination of the invention includes at leastone anticancer alkylating agent as chemotherapeutic agent.

An anticancer alkylating agent refers to an alkylating agent havinganticancer activity, and the term “alkylating agent” herein generallyrefers to an agent giving an alkyl group in the alkylation reaction inwhich a hydrogen atom of an organic compound is substituted with analkyl group.

Examples of anticancer alkylating agents include nitrogen mustardN-oxide, cyclophosphamide, ifosfamide, melphalan, busulfan,mitobronitol, carboquone, thiotepa, rammustine, nimustine, temozolomideand carmustine.

Anticancer Antimetabolite

In one embodiment, the combination of the invention includes at leastone anticancer antimetabolite as chemotherapeutic agent.

An anticancer antimetabolite refers to an antimetabolite havinganticancer activity, and the term “antimetabolite” herein includes, in abroad sense, substances which disturb normal metabolism and substanceswhich inhibit the electron transfer system to prevent the production ofenergy-rich intermediates, due to their structural or functionalsimilarities to metabolites that are important for living organisms(such as vitamins, coenzymes, amino acids and saccharides).

Examples of anticancer antimetabolites include methotrexate,6-mercaptopurine riboside, mercaptopurine, 5-fluorouracil (also called“5-FU”), tegafur, doxifluridine, carmofur, cytarabine, cytarabineocfosfate, enocitabine, S-1, gemcitabine, fludarabine and pemetrexeddisodium. Preferably the anticancer antimetabolite is selected from5-FU, gemcitabine and pemetrexed.

Anticancer Antibiotic

In one embodiment, the combination of the invention includes at leastone anticancer antibiotic as chemotherapeutic agent.

An “anticancer antibiotic” refers to an antibiotic having anticanceractivity, and the “antibiotic” herein includes substances that areproduced by microorganisms or by partial or total synthesis, andderivatives thereof; and inhibit cell growth and other functions ofmicroorganisms and of other living organisms.

Examples of anticancer antibiotic include actinomycin D, doxorubicin,daunorubicin, neocarzinostatin, bleomycin, peplomycin, mitomycin C,aclarubicin, pirarubicin, epirubicin, zinostatin stimalamer, idarubicin,sirolimus and valrabicin. Preferably, the anticancer antibiotic isdoxorubicin.

Plant-Derived Anticancer Agent

In one embodiment, the combination of the invention includes at leastone plant-derived anticancer agent as chemotherapeutic agent.

A “plant-derived anticancer agent” as used in the specification includescompounds having anticancer activities which originate from plants, orcompounds prepared by applying chemical modification to the foregoingcompounds.

Examples of plant-derived anticancer agent include vincristine,vinblastine, vindesine, etoposide, sobuzoxane, docetaxel, paclitaxel,nab-paclitaxel and vinorelbine. Preferably, the plant-derived anticanceragent is docetaxel.

Anticancer Platinum Coordination Compound

In one embodiment, the combination of the invention includes at leastone anticancer platinum coordination compound as chemotherapeutic agent.

An “anticancer platinum coordination compound” refers to a platinumcoordination compound having anticancer activity, and the term “platinumcoordination compound” herein refers to a platinum coordination compoundwhich provides platinum in ion form.

Preferred platinum compounds include cisplatin;cis-diamminediaquoplatinum (O)-ion; chloro(diethylenetriamine)-platinum(II) chloride; dichloro(ethylenediamine)-platinum (II); diamine(1,1-cyclobutanedicarboxylato) platinum (II) (carboplatin); spiroplatin;iproplatin; diamine(2-ethylmalonato)platinum (II);ethylenediaminemalonatoplatinum (H);aqua(1,2-diaminodicyclohexane)sulfatoplatinum (II);aqua(1,2-diaminodicyclohexane)malonatoplatinum (II);(1,2-diaminocyclohexane)malonatoplatinum (II);(4-carboxyphthalato)(1,2-diaminocyclohexane) platinum (II);(1,2-diaminocyclohexane)-(isocitrato)platinum (II);(1,2-diaminocyclohexane)oxalatoplatinum (II); ormaplatin; tetraplatin;carboplatin, nedaplatin and oxaliplatin. Preferably the anticancerplatinum coordination compound is selected from carboplatin andoxaliplatin.

Parp Inhibitors

In one embodiment, the combination of the invention includes at leastone Parp inhibitor as chemotherapeutic agent.

A “Parp inhibitor” refers to an inhibitor of the enzyme poly ADP ribosepolymerase (PARP). This enzyme is important for repairing single-strandbreaks in the DNA. If such breaks remain unrepaired until DNA isreplicated, then the replication can cause double strand breaks to form.PARP inhibitors thus enable to cause multiple double strand breaks toform in tumors, leading to the death of the tumor cells.

Examples of Parp inhibitors include olaparib, rucaparib, niraparib,veliparib, pamiparib, iniparib, and talazoparib.

Anti-Hormone-Sensitive Cancer Agent

In one embodiment, the combination of the invention includes at leastone anti-hormone-sensitive cancer agent as chemotherapeutic agent.

An “anti-hormone-sensitive cancer agent” refers to an anticancer agenthaving an activity against hormone-sensitive cancers. Examples ofanti-hormone-sensitive cancer agents include anti-androgens, GnRHagonists and GnRH antagonists.

“Anti-androgens” refer to a class of drugs that prevent androgens liketestosterone and dihydrotestosterone (DHT) from mediating theirbiological effects in the body. Anti-androgens may be used for exampleto treat prostate cancer. Examples of anti-androgens includebicalutamide, flutamide, nilutamide, apalutamide, enzalutamide andabiraterone.

“Gonadotropin-releasing hormone agonists” (GnRH agonist) refer to aclass of drugs which affects gonadotropins and sex hormones. They may beused to lower sex hormone levels in the treatment of hormone-sensitivecancers such as prostate cancer and breast cancer. Examples of GnRHagonists include goserelin, leuprorelin and triptorelin.

“Gonadotropin-releasing hormone antagonists” (GnRH antagonist) refer toa class of drugs that antagonize the action of gonadotropin-releasinghormone (GnRH). They may be used for example in the treatment ofprostate cancer. An example of GnRH antagonist is degarelix.

Combinations of Chemotherapeutic Agents

Combinations of chemotherapeutic agents may be used as the secondcomponent of the combination of the invention.

For example, the combination known as folfox may be used. Folfoxcomprises the combined use of fluorouracil (antimetabolite), oxaliplatin(platinum compound) and folinic acid (chemoprotectant).

A combination consisting of carboplatin (platinum compound) andpaclitaxel (plant-derived agent) may alternatively be used. Anotherexample is a combination consisting of gemcitabine (antimetabolite) andnab-paclitaxel (plant-derived agent).

In one embodiment, the combination of chemotherapeutic agents isselected from:

-   -   (i) a combination consisting of folinic acid, fluorouracil and        oxaliplatin (folfox);    -   (ii) a combination consisting of carboplatin and paclitaxel; and    -   (iii) a combination consisting of gemcitabine and        nab-paclitaxel.

Antiangiogenic Agent

In one embodiment, the combination of the invention includes at leastone antiangiogenic agent as anticancer agent.

Angiogenesis, i.e. growth of new blood vessels, plays an important rolein the development of tumors and the progression of malignancies.Inhibiting angiogenesis has been shown to suppress tumor growth andmetastasis. The most prominent target of antiangiogenic agents isvascular endothelial growth factor (VEGF) and its receptors. Severalother factors are of interest as well, including integrins, matrixmetalloproteinases, and endogenous antiangiogenic factors.

Antiangiogenic agents thus include VEGF inhibitors, integrins inhibitorsand matrix metalloproteinases inhibitors.

Examples of antiangiogenic agents include Ramucirumab, IMC-18F1,Bevacizumab, Ziv-aflibercept, Sorafenib, Sunitinib, Axitinib,Nintedanib, Regorafenib, Pazobanib, Cabozantinib, Vandetanib andThalidomide. In a specific embodiment, the antiangiogenic agent is aVEGF inhibitor, for example Ramucirumab.

Multidrug Resistance-Associated Proteins Inhibitors

In one embodiment, the combination of the invention includes at leastone multidrug resistance-associated protein inhibitor as anticanceragent.

Multidrug resistance-associated proteins (MRP/ABCC) are a subfamily ofATP-binding cassette transporters, which are capable of actively pumpinga wide variety of organic anionic compounds across the plasma membraneagainst their concentration gradient. These proteins are involved inmulti-drug resistance by transporting a wide variety of drugs outsidecells, among which anticancer drugs. Inhibiting multidrugresistance-associated proteins can thus improve efficacy of anticancerdrugs.

Examples of multidrug resistance-associated protein inhibitor includeinhibitors of MRP4/ABCC4, inhibitors of MRP5/ABCC5 and inhibitors ofMRP8/ABCC11.

Radiotherapeutic Agents—Radiation Therapy

In one embodiment, the combination of the invention includes at leastone radiotherapeutic agent as anticancer agent.

“Radiation therapy” refers to a method of treatment of cancer employingvarious radiations such as X-ray, γ-ray, neutron ray, electron beam,proton beam and radiation sources. It is used as part of cancertreatment to control or kill malignant cells. Radiation therapy may becurative in a number of types of cancer if they are localized to onearea of the body. It may also be used as part of adjuvant therapy, toprevent tumor recurrence after surgery to remove a primary malignanttumor.

The three main divisions of radiation therapy are: external beamradiation therapy (EBRT or XRT); brachytherapy or sealed sourceradiation therapy; and systemic radioisotope therapy (RIT) or unsealedsource radiotherapy. The differences relate to the position of theradiation source; external is outside the body, brachytherapy usessealed radioactive sources placed precisely in the area under treatment,and systemic radioisotopes are given by infusion or oral ingestion.Particle therapy is a special case of external beam radiation therapywhere the particles are protons or heavier ions. Radiations may bedelivered by a linear accelerator.

Systemic radioisotope therapy (RIT) is a form of targeted therapy.Targeting can be due to the chemical properties of the isotope such asradioiodine which is specifically absorbed by the thyroid gland athousand fold better than other bodily organs. Targeting can also beachieved by attaching the radioisotope to another molecule or antibodyto guide it to the target tissue, forming a radiopharmaceutical agent.

In order to enhance the radiosensitivity of the cancer, radiosensitizingagents may be administered during a radiation therapy. Examples ofradiosensitizing agents include: Cisplatin, Nimorazole, and Cetuximab.

Thus, in one embodiment, radiotherapeutic agent is selected from sealedradiation sources, radioisotopes, radiopharmaceutical agents,radiosensitizing agents and the like useful in the course of radiationtherapy.

In another embodiment, the invention also provides the use of the A2ARinhibitor as described above, in combination with radiation therapy,including radiation therapy performed by external beam radiations orX-ray radiations; brachytherapy; and systemic radioisotope therapy.

Combinations

In one embodiment, the combination of the invention comprises at leastone A2AR inhibitor as defined above and at least one anticancer agent asdefined above.

In a specific embodiment, the combination of the invention comprises atleast one A2AR inhibitor as defined above and at least oneimmunotherapeutic agent as defined above.

In a specific embodiment, the combination of the invention comprises atleast one A2AR inhibitor as defined above and at least one checkpointinhibitor as defined above, preferably an inhibitor of PD-1, PD-L1,CTLA-4 or of TIGIT, or any mixture thereof.

In a specific embodiment, the combination of the invention comprises atleast one A2AR inhibitor as defined above and at least oneadenosine-producing enzymes inhibitor as defined above, preferably atleast one inhibitor of CD39, such as for example ARL67156 and POM-1.

In a specific embodiment, the combination of the invention comprises atleast one A2AR inhibitor as defined above and at least onechemotherapeutic agent as defined above.

In a specific embodiment, the combination of the invention comprises atleast one A2AR inhibitor as defined above and at least one anticancerantibiotic as defined above, such as for example doxorubicin.

In a specific embodiment, the combination of the invention comprises atleast one A2AR inhibitor as defined above and at least one anticancerplatinum coordination compound as defined above, such as for exampleoxaliplatin.

In a specific embodiment, the combination of the invention comprises atleast one A2AR inhibitor as defined above, at least oneimmunotherapeutic agent as defined above and at least onechemotherapeutic agent as defined above.

In a specific embodiment, the combination of the invention comprises atleast one A2AR inhibitor as defined above, at least one checkpointinhibitor as defined above and at least one chemotherapeutic agent asdefined above. In a specific embodiment, the combination of theinvention comprises at least one A2AR inhibitor as defined above, atleast one inhibitor of PD-L1, CTLA-4 or TIGIT and at least onechemotherapeutic agent as defined above. In a specific embodiment, thecombination of the invention comprises at least one A2AR inhibitor asdefined above, at least one checkpoint inhibitor as defined above and atleast one. In a specific embodiment, the combination of the inventioncomprises at least one A2AR inhibitor as defined above, at least oneinhibitor of PD-L1, CTLA-4 or TIGIT as defined above and at least oneanticancer antibiotic as defined above, such as for example doxorubicin.

In a specific embodiment, the combination of the invention comprises atleast one A2AR inhibitor as defined above and at least two checkpointinhibitor as defined above. In a specific embodiment, the combination ofthe invention comprises at least one A2AR inhibitor as defined above, atleast one inhibitor of PD-L1 as defined above and at least one inhibitorof TIGIT as defined above.

Pharmaceutical Composition

The invention further relates to a pharmaceutical composition comprisingthe combination of the invention.

In one embodiment, the pharmaceutical composition comprises:

-   -   (a) at least one A2AR inhibitor,    -   (b) at least one anticancer agent, and    -   (c) at least one pharmaceutically acceptable carrier, diluent,        excipient and/or adjuvant.

In a preferred embodiment, the invention provides a pharmaceuticalcomposition comprising:

-   -   (a) at least one A2AR inhibitor being a thiocarbamate        derivative, more preferably a thiocarbamate derivative of        Formula (I) or a pharmaceutically acceptable salt or solvate        thereof, as defined above;    -   (b) at least one anticancer agent as defined above, such as for        example immunotherapeutic agents, chemotherapeutic agents,        antiangiogenic agents, multidrug resistance-associated proteins        inhibitors, radiotherapeutic agents, or any combination thereof,        and    -   (c) at least one pharmaceutically acceptable carrier, diluent,        excipient and/or adjuvant.

The at least one pharmaceutically acceptable carrier, diluent, excipientand/or adjuvant for use in the preparation of the administration formswill be clear to the skilled person; reference is made to the latestedition of Remington's Pharmaceutical Sciences.

Especially, the pharmaceutical composition comprising the combination ofthe invention can optionally contain such inactive substances that arecommonly used in pharmaceutical formulations, such as for examplecosolvents, lipid carrier, antioxidants, surfactants, wetting agents,emulsifying agents, buffering agents, pH modifying agents, preservingagents (or preservating agents), isotonifiers, stabilizing agents,granulating agents or binders, precipitation inhibitors, lubricants,disintegrants, glidants, diluents or fillers, adsorbents, dispersingagents, suspending agents, bulking agents, release agents, sweeteningagents, flavoring agents, and the like.

In a preferred embodiment, the pharmaceutical composition comprising thecombination of the invention comprises one or more pharmaceuticallyacceptable cosolvent. Preferably cosolvents are selected from caprylicacid, polyethylene glycol (PEG), propylene glycol, ethanol,dimethylsulfoxide, dimethylacetamide, dimethylisosorbide and mixturesthereof. In a specific embodiment, the pharmaceutical composition of theinvention comprises caprylic acid and/or PEG. Advantageously, when thecomposition comprises PEG as cosolvent, PEG is of low molecular weight,preferably PEG is PEG 400. In an alternative embodiment, when thecomposition comprises PEG, it is of a moderate molecular weight,preferably PEG 3350.

In a specific embodiment, the pharmaceutical composition comprising thecombination of the invention comprises one or more pharmaceuticallyacceptable lipid carrier. In a preferred embodiment, the lipid carrieris lauroyl polyoxyl-32 glycerides. This excipient corresponds toGelucire® 44/14 manufactured by Gattefossé (Saint-Priest—France). Thisexcipient is also known under the following references: lauroylpolyoxyl-32 glycerides NF/USP (NF: National Formulary; USP: USPharmacopeia); lauroyl macrogol-32 glycerides EP (EuropeanPharmacopeia); hydrogenated coconut PEG-32 esters (INCI); CAS number57107-95-6. Gelucire® 44/14 corresponds to a well-definedmulti-constituent substance constituted of mono-, di- and triglyceridesand PEG-32 mono- and diesters of lauric acid (C₁₂). Gelucire® 44/14 hasa melting point ranging from 42.5° C. to 47.5° C. (with a mean at 44°C.) and an hydrophilic/lipophilic balance (HLB) value of 14.

In another embodiment, the lipid carrier is Vitamin E TPGS. Thisexcipient is also known under the following references: D-α-Tocopherolpolyethylene glycol-1000 succinate; Tocophersolan; Tocofersolan; VEGS;α-[4-[[(2R)-3,4-dihydro-2,5,7,8-tetramethyl-2-[(4R,8R)-4,8,12-trimethyltridecyl]-2H-1-benzopyran-yl]oxy]-1,4-dioxobutyl]-ω-hydroxy-poly(oxy-1,2-ethanediyl);Vitamin E PEG succinate and is formed from Vitamin E which is conjugatedto polyethylene glycol 1000 via a succinic acid linker. Vitamin E TPGShas melting point in the range 37-41° C. and an hydrophilic/lipophilicbalance (HLB) value of 13.

In one embodiment, the pharmaceutical composition comprising thecombination of the invention further comprises one or more antioxidant;preferably the antioxidant is selected from butylated hydroxytoluene(BHT), butylated hydroxyanisole (BHA), citric acid, sodiummetabisulfite, ascorbic acid, methionine and vitamin E; more preferablythe antioxidant is BHT.

In some embodiments, surfactants are added, such as for examplepolyethylene glycols, polyoxyethylene sorbitan fatty acid esters,sorbitan esters, sodium docusate, sodium lauryl sulfate, polysorbates(20, 80, etc.), poloxamers (188, 407 etc.), pluronic polyols,polyoxyethylene sorbitan monoethers (TWEEN®-20, TWEEN®-80, etc.),vitamin E TPGS (Vitamin E polyethylene glycol succinate), cremophor RH40(polyoxyl 40 hydrogenated castor oil), cremophor EL (polyoxyl 35hydrogenated castor oil), polyethylene glycol 660 12-monostearate,solutol HS15 (Polyoxyethylated 12-hydroxystearic acid), labrasol(caprylocaproyl polyoxyl-8 glycerides), labrafil M1944 (Oleoylpolyoxyl-6 glycerides), polylactide polyethylene glycol copolymer,polyvinyl caprolactan-polyvinyl acetate-polyethylene glycol graftcopolymer (Soluplus®).

In some embodiments, wetting agents are added, such as for examplesodium lauryl sulphate, vitamin E TPGS, sodium docusate, polysorbate 80,poloxamer 407. A preferred wetting agent is poloxamer 407.

In some embodiments, emulsifying agents are added, such as for examplecarbomer, carrageenan, lanolin, lecithin, mineral oil, oleic acid, oleylalcohol, pectin, poloxamer, polyoxyethylene sorbitan fatty acid esters,sorbitan esters, triethanolamine, propylene glycol monolaurate,propylene glycol dilaurate, propylene glycol monocaprylate. Preferredemulsifying agents are for example poloxamer, propylene glycolmonolaurate, propylene glycol dilaurate, and propylene glycolmonocaprylate.

In some embodiments, buffering agents are used to help to maintain thepH in the range that approximates physiological conditions Suitablebuffering agents include both organic and inorganic acids and saltsthereof, such as citrate buffers (e.g., monosodium citrate-disodiumcitrate mixture, citric acid-trisodium citrate mixture, citricacid-monosodium citrate mixture, etc.), succinate buffers (e.g.,succinic acid-monosodium succinate mixture, succinic acid-sodiumhydroxide mixture, succinic acid-disodium succinate mixture, etc.),tartrate buffers (e.g., tartaric acid-sodium tartrate mixture, tartaricacid-potassium tartrate mixture, tartaric acid-sodium hydroxide mixture,etc.), fumarate buffers (e.g., fumaric acid-monosodium fumarate mixture,fumaric acid-disodium fumarate mixture, monosodium fumarate-disodiumfumarate mixture, etc.), gluconate buffers (e.g., gluconic acid-sodiumglyconate mixture, gluconic acid-sodium hydroxide mixture, gluconicacid-potassium glyuconate mixture, etc.), oxalate buffer (e.g., oxalicacid-sodium oxalate mixture, oxalic acid-sodium hydroxide mixture,oxalic acid-potassium oxalate mixture, etc.), lactate buffers (e.g.,lactic acid-sodium lactate mixture, lactic acid-sodium hydroxidemixture, lactic acid-potassium lactate mixture, etc.) and acetatebuffers (e.g., acetic acid-sodium acetate mixture, acetic acid-sodiumhydroxide mixture, etc.). Additionally, phosphate buffers, histidinebuffers and trimethylamine salts such as Tris can be used.

In some embodiments, pH modifiers are added, such as for example sodiumhydroxide, sodium bicarbonate, magnesium oxide, potassium hydroxide,meglumine, sodium carbonate, citric acid, tartaric acid, ascorbic acid,fumaric acid, succinic acid and malic acid;

In some embodiments, preservatives agents are added to retard microbialgrowth. Suitable preservatives for use with the present disclosureinclude phenol, benzyl alcohol, meta-cresol, methyl paraben, propylparaben, octadecyldimethylbenzyl ammonium chloride, benzalconium halides(e.g., chloride, bromide, and iodide), hexamethonium chloride, and alkylparabens such as methyl or propyl paraben, catechol, resorcinol,cyclohexanol, and 3-pentanol.

In some embodiments, isotonifiers sometimes known as “stabilizers” areadded and include polyhydric sugar alcohols, for example trihydric orhigher sugar alcohols, such as glycerin, erythritol, arabitol, xylitol,sorbitol and mannitol. Stabilizers refer to a broad category ofexcipients which can range in function from a bulking agent to anadditive which solubilizes the therapeutic agent or helps to preventdenaturation or adherence to the container wall or helps to inhibit theprecipitation, particle growth or agglomeration of the activeingredient. Typical stabilizers can be polyhydric sugar alcohols(enumerated above); amino acids such as arginine, lysine, glycine,glutamine, asparagine, histidine, alanine, ornithine, L-leucine,2-phenylalanine, glutamic acid, threonine, etc.; organic sugars or sugaralcohols, such as lactose, trehalose, stachyose, mannitol, sorbitol,xylitol, ribitol, myoinisitol, galactitol, glycerol and the like,including cyclitols such as inositol; polyethylene glycol; amino acidpolymers; sulfur containing reducing agents, such as urea, glutathione,thioctic acid, sodium thioglycolate, thioglycerol, α-monothioglyceroland sodium thio sulfate; low molecular weight polypeptides (e.g.,peptides of 10 residues or fewer); proteins such as human serum albumin,bovine serum albumin, gelatin or immunoglobulins; hydrophylic polymers,such as polyvinylpyrrolidone; poloxamer 407; cellulose derivatives suchas hydroxypropylmethylcellulose, hydroxypropylmethylcellulose phthalateor hydroxypropylmethylcellulose acetate succinate;carboxymethylcellulose (Na/Ca); monosaccharides, such as xylose,mannose, fructose, glucose; disaccharides such as lactose, maltose,sucrose and trisaccacharides such as raffinose; polysaccharides such asdextran; polyethylene glycol methyl ether-block-poly(D-L-lactide)copolymer; poly(butyl methacrylate-co-(2-dimethylaminoethyl)methacrylate-co-methyl methacrylate) 1:2:1. Preferred stabilizers arefor example glycerol; polyethylene glycol; polyvinylpyrrolidone;cellulose derivatives such as hydroxypropylmethylcellulose,hydroxypropylmethylcellulose phthalate or hydroxypropylmethylcelluloseacetate succinate; carboxymethylcellulose (Na/Ca); polyethylene glycolmethyl ether-block-poly(D-L-lactide) copolymer; and poly(butylmethacrylate-co-(2-dimethylaminoethyl) methacrylate-co-methylmethacrylate) 1:2:1, polyvinyl caprolactam-polyvinylacetate-polyethylene glycol graft copolymer, polyvinylpyrrolidonepolyvinylacetate copolymer.

In some embodiments granulating agent/binder(s) are added, such as forexample starch, gums (inclusive of natural, semisynthetic andsynthetic), microcrystalline cellulose, ethyl cellulose,methylcellulose, hydroxypropylcellulose, polymers such as povidone,polyvinylpyrrolidone polyvinylacetate copolymer and the like. Preferredgranulating agents are for example methylcellulose,hydroxypropylcellulose, povidone and polyvinylpyrrolidonepolyvinylacetate copolymer.

In some embodiments precipitation inhibitors are added, such as forexample water soluble derivatives of cellulose includinghydroxypropylmethylcellulose and methylcellulose, and water solublepolymers such as polyvinylpyrrolidone, polyvinylpyrrolidonepolyvinylacetate copolymer, polyvinyl caprolactam-polyvinylacetate-polyethylene glycol graft copolymer or poloxamer 407. Apreferred precipitation inhibitor is hydroxypropylmethylcellulose.

In some embodiments lubricants are added, such as for example magnesiumstearate, glyceryl esters, behenoyl polyoxyl-8 glycerides Nf (CompritolHD5 ATO), sodium stearyl fumarate and the like.

In some embodiments disintegrants are added, such as for examplesynthetics like sodium starch glycolate, cross povidone, crosscarmellose sodium, kollidon CL, and natural origin such as locust beangum and the like.

In some embodiments glidants are added, such as for example talc,magnesium stearate, colloidal silicon dioxide, starch and the like.

In some embodiments diluents (or fillers) are added, such as for exampledextrose, lactose, mannitol, microcrystalline cellulose, sorbitol,sucrose, dibasic calcium phosphate, calcium sulphate dehydrate, starchand the like.

In some embodiments adsorbents are added, such as for example silicondioxide, purified aluminium silicate and the like.

In some embodiments, the pharmaceutical composition comprising thecombination of the invention is in the form of tablets and tabletingexcipients are added, such as for example granulating agents, binders,lubricants, disintegrants, glidants, diluents, adsorbents and the like.

In some embodiments the pharmaceutical composition comprising thecombination of the invention is in the form of capsules, in which thecapsule shells are constructed from gelatin or from non-animal derivedproducts such as cellulose and its derivatives such ashydroxypropylmethylcellulose. Other ingredients may be included in thecapsule shells such as polyethyleneglycol to act as plasticizer;pigments such as titanium dioxide or iron oxide to provide opacity andcolour differentiation; lubricants such as carnauba wax; gelling agentssuch as carrageenan and wetting agents such as sodium lauryl sulphate.In one embodiment, the pharmaceutical composition comprising thecombination of the invention is formulated as capsules, wherein thecapsule shells are constructed from gelatin and wherein additionalcomponents are optionally included in the capsule shells, such as forexample polyethylene glycol and sodium lauryl sulphate.

By means of non-limiting examples, the pharmaceutical compositioncomprising the combination may be in a form suitable for oraladministration, for parenteral administration (such as by intravenous,intramuscular or subcutaneous injection or intravenous infusion), fortopical administration (including ocular), for rectal administration,for administration by inhalation, by a skin patch, by an implant, by asuppository, etc. Such suitable administration forms—which may be solid,semi-solid or liquid, depending on the manner of administration—as wellas methods and carriers, diluents and excipients for use in thepreparation thereof, will be clear to the skilled person; reference ismade to the latest edition of Remington's Pharmaceutical Sciences.

The compositions may be formulated so as to provide rapid, sustained ordelayed release of the active compound(s) contained therein.

According to one embodiment, the pharmaceutical composition comprisingthe combination is in an adapted form for an oral administration. Formsadapted to oral administration may be solid, semi-solid or liquid. Somepreferred, but non-limiting examples of such forms include liquid, pasteor solid compositions, and more particularly tablets, tablets formulatedfor extended or sustained release, capsules (including soft and hardgelatin capsules), pills, dragees, lozenges, sachets, cachets, powder,liquids, gels, syrups, slurries, elixirs, emulsions, solutions, andsuspensions.

According to another embodiment, the pharmaceutical compositioncomprising the combination is in an adapted form for an injection,especially to be injected to the subject by intravenous, intramuscular,intraperitoneal, intrapleural, subcutaneous, transdermal injection orinfusion.

Sterile injectable forms of the pharmaceutical composition of theinvention include sterile injectable solutions and sterile packagedpowders (which are usually reconstituted prior to use) foradministration as a bolus and/or for continuous administration.

Sterile injectable forms of the pharmaceutical composition of theinvention may be a solution or an aqueous or oleaginous suspension.These suspensions may be formulated according to techniques known in theart using suitable dispersing or wetting agents and suspending agents.The sterile injectable preparation may also be a sterile injectablesolution or suspension in a non-toxic pharmaceutically acceptablediluent or solvent. Among the acceptable vehicles and solvents that maybe employed are water, Ringer's solution and isotonic sodium chloridesolution. In addition, sterile, fixed oils are conventionally employedas a solvent or suspending medium. For this purpose, any bland fixed oilmay be employed including synthetic mono- or diglycerides. Fatty acids,such as oleic acid and its glyceride derivatives are useful in thepreparation of injectables, as are natural pharmaceutically acceptableoils, such as olive oil or castor oil, especially in theirpolyoxyethylated versions. These oil solutions or suspensions may alsocontain a long-chain alcohol diluent or dispersant, such ascarboxymethyl cellulose or similar dispersing agents that are commonlyused in the formulation of pharmaceutically acceptable dosage formsincluding emulsions and suspensions. Other commonly used surfactants,such as Tweens, Spans and other emulsifying agents or bioavailabilityenhancers which are commonly used in the manufacture of pharmaceuticallyacceptable solid, liquid, or other dosage forms may also be used for thepurposes of formulation. According to another embodiment, thepharmaceutical composition comprising the combination of the inventionis in an adapted form for a topical administration. Examples of formsadapted for topical administration include, without being limited to,liquid, paste or solid compositions, and more particularly aqueoussolutions, drops, dispersions, sprays, ointments, cremes, lotions,microcapsules, micro- or nanoparticles, polymeric patch, orcontrolled-release patch, and the like.

According to another embodiment, the pharmaceutical compositioncomprising the combination of the invention is in an adapted form for arectal administration. Examples of forms adapted for rectaladministration include, without being limited to, suppository, microenemas, enemas, gel, rectal foam, cream, ointment, and the like.

According to another embodiment, the pharmaceutical compositioncomprising the combination of the invention is in an adapted form for anadministration by inhalation. Examples of forms adapted foradministration by inhalation include, without being limited to aerosols.

The pharmaceutical preparations of the invention are preferably in aunit dosage form, and may be suitably packaged, for example in a box,blister, vial, bottle, sachet, ampoule or in any other suitablesingle-dose or multi-dose holder or container (which may be properlylabeled); optionally with one or more leaflets containing productinformation and/or instructions for use.

Kit of Parts

The invention further relates to a kit of parts comprising thecombination of the invention.

In one embodiment, the kit of parts of the invention comprises:

-   -   (a) a first part comprising at least one A2AR inhibitor, and    -   (b) a second part comprising at least one anticancer agent.

In a preferred embodiment, the invention provides a kit of partscomprising:

-   -   (a) a first part comprising at least one A2AR inhibitor being a        thiocarbamate derivative, more preferably a thiocarbamate        derivative of Formula (I)

-   -   -   or a pharmaceutically acceptable salt or solvate thereof, as            defined above; and

    -   (b) a second part comprising at least one anticancer agent as        defined above, such as for example immunotherapeutic agents,        chemotherapeutic agents, antiangiogenic agents, multidrug        resistance-associated proteins inhibitors, radiotherapeutic        agents, or any combination thereof.

In one embodiment, the first part comprises a pharmaceutical compositioncomprising an A2AR inhibitor, preferably a thiocarbamate derivative ofFormula (I) as defined above, and at least one pharmaceuticallyacceptable carrier, diluent, excipient and/or adjuvant.

Pharmaceutically acceptable carrier, diluent, excipient and/or adjuvantof the pharmaceutical composition of the first part of the kit of partmay be those listed above with regards to the pharmaceutical compositionof the invention.

Similarly, the dosage form and the administration route of thepharmaceutical composition of the first part of the kit of part may bethose listed above with regards to the pharmaceutical composition of theinvention.

In one embodiment, the second part comprises at least one anticanceragent as defined above. Depending on the type of anticancer agent, thesecond part of the kit may be under the form of a pharmaceuticalcomposition. Excipients, dosage form and administration route of such apharmaceutical composition will be clear to the skilled person(reference is made to the latest edition of Remington's PharmaceuticalSciences), and especially may be those listed above with regards to thepharmaceutical composition of the invention.

According to one embodiment, the kit of the invention may comprise oneor more further parts comprising one or more further anticancer agents.For example, the kit may comprise (a) a first part comprising an A2ARinhibitor of Formula (I); (b) a second part comprising animmunotherapeutic agent; and (c) a third part comprising achemotherapeutic agent. In another embodiment, the kit may comprise (a)a first part comprising an A2AR inhibitor of Formula (I); (b) a secondpart comprising a checkpoint inhibitor; and (c) a third part comprisinga chemotherapeutic agent. In another embodiment, the kit may comprise(a) a first part comprising an A2AR inhibitor of Formula (I); (b) asecond part comprising a checkpoint inhibitor; and (c) a third partcomprising a different checkpoint inhibitor.

As developed below, the administration of the different parts of the kitmay be made simultaneously or timely staggered, with similar ordifferent timing of administration (i.e. similar or different numbers ofadministration of each component), either at the same site ofadministration or at different sites of administration, under similar ofdifferent dosage forms.

Regimen and Doses

In the context of the present invention, the administration of the A2ARinhibitor and the anticancer agent may occur either simultaneously ortimely staggered, with similar or different timing of administration(i.e. similar or different numbers of administration of each component),either at the same site of administration or at different sites ofadministration, under similar of different dosage forms, as furtheroutlined below.

To ensure that the separate mechanisms elicited by the A2AR inhibitorand the anticancer agent are not negatively influenced by each other,the anticancer agent and the A2AR inhibitor are preferably administeredseparated in time (in a time-staggered manner), i.e. sequentially,and/or are administered at different administration sites. This meansthat the A2AR inhibitor may be administrated e.g. prior, concurrent orsubsequent to the anticancer agent, or vice versa. Alternatively oradditionally, the A2AR inhibitor and the anticancer agent may beadministered at different administration sites, or at the sameadministration site, preferably, when administered in a time staggeredmanner.

In one embodiment, the A2AR inhibitor is to be administered prior toand/or concomitantly with an immunotherapeutic agent as describedhereinabove. In one embodiment, the immunotherapeutic agent is acheckpoint inhibitor and the A2AR inhibitor is to be administered priorto the day or on the same day that the checkpoint inhibitor as describedhereinabove is administered.

In one embodiment, the A2AR inhibitor is to be administered prior toand/or concomitantly with an immunotherapeutic agent as describedhereinabove and continuously thereafter.

In one embodiment, the A2AR inhibitor is to be administered prior to orconcomitantly with an immunotherapeutic agent as described hereinaboveand subsequently for at least 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 daysthereafter. In another embodiment, the A2AR inhibitor is to beadministered prior to or concomitantly with an immunotherapeutic agentas described hereinabove and subsequently for at least 1, 2, 3, 4, 5, 6,7, 8, 9, or 10 weeks thereafter. In another embodiment, the A2ARinhibitor is to be administered prior to or concomitantly with animmunotherapeutic agent as described hereinabove and subsequently for atleast 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 months thereafter.

In one embodiment, the immunotherapeutic agent is a checkpoint inhibitorand the A2AR inhibitor is to be administered prior to or concomitantlywith said checkpoint inhibitor.

In one embodiment, the immunotherapeutic agent is a checkpoint inhibitorand the A2AR inhibitor is to be administered prior to or concomitantlywith said checkpoint inhibitor and continuously thereafter. In oneembodiment, the immunotherapeutic agent is a checkpoint inhibitor andthe A2AR inhibitor is to be administered prior to or concomitantly withsaid checkpoint inhibitor and subsequently for at least 1, 2, 3, 4, 5,6, 7, 8, 9, or 10 weeks thereafter.

Depending on the condition to be prevented or treated and the form ofadministration, the combination of the invention may be administered asa single daily dose, divided over one or more daily doses.

According to one embodiment, a therapeutically effective dose of A2ARinhibitor as described hereinabove is to be administered for use in thetreatment of a cancer in a subject in need thereof, wherein said A2ARinhibitor is used in combination with an anticancer agent, such as forexample an immunotherapeutic agent. Thus, in one embodiment, thepharmaceutical combination or kit of parts of the invention comprises atherapeutically effective dose of A2AR inhibitor as describedhereinabove and a therapeutically effective dose of anticancer agent asdescribed hereinabove.

It will be understood that the total daily usage of A2AR inhibitor andanticancer agent will be decided by the attending physician within thescope of sound medical judgment. The specific dose for any particularsubject will depend upon a variety of factors such as the cancer to betreated; the age, body weight, general health, sex and diet of thepatient; and like factors well-known in the medical arts.

In one embodiment, the subject is a mammal, preferably a human, and thedose of A2AR inhibitor, preferably a therapeutically effective dose, isa dose ranging from about 0.01 mg per kilo body weight (mg/kg) to about5 mg/kg, preferably about 0.08 mg/kg to about 3.3 mg/kg, more preferablyabout 0.15 mg/kg to about 1.7 mg/kg.

In one embodiment, the subject is a mammal, preferably a human, and thedose of A2AR inhibitor, preferably a therapeutically effective dose, isa dose ranging from about 0.01 mg per kilo body weight per day(mg/kg/day) to about 5 mg/kg/day, preferably about 0.08 mg/kg/day toabout 3.3 mg/kg/day, more preferably about 0.15 mg/kg/day to about 1.7mg/kg/day.

In one embodiment, the subject is a mammal, preferably a human, and thedose of A2AR inhibitor, preferably a therapeutically effective dose, isa dose ranging from about 1 mg to about 500 mg, preferably about 5 mg toabout 200 mg, more preferably from about 10 mg to about 100 mg.

In one embodiment, the subject is a mammal, preferably a human, and thedose of A2AR inhibitor, preferably a therapeutically effective dose, isa dose ranging from about 1 mg to about 500 mg per administration,preferably about 5 mg to about 200 mg per administration, morepreferably from about 10 mg to about 100 mg per administration.

In one embodiment, the subject is a mammal, preferably a human, and thedose of A2AR inhibitor, preferably a therapeutically effective dose, isa daily dose ranging from about 1 mg to about 500 mg, preferably about 5mg to about 200 mg, more preferably from about 10 mg to about 100 mg.

In one embodiment, the subject is a mammal, preferably a human, and thedose of A2AR inhibitor, preferably a therapeutically effective dose, isa daily dose to be administered in one, two, three or more takes. In oneembodiment, the subject is a mammal, preferably a human, and the dose ofA2AR inhibitor, preferably a therapeutically effective dose, is a dailydose to be administered in one or two takes.

Uses

Another object of this invention is the use of the combination of theinvention as a medicament. Thus, in one embodiment, the inventionprovides the use of the combination of the invention for themanufacturing of a medicament. Especially, the invention provides theuse of the pharmaceutical composition of the invention or the kit of theinvention for the manufacturing of a medicament.

Especially, the invention provides the combination, the pharmaceuticalcomposition or the kit of parts of the invention, for use in thetreatment and/or prevention of cancer.

In one embodiment, the invention relates to a treatment and/orprevention of cancer, which comprises administering to a mammal speciesin need thereof a therapeutically effective amount of the combination,pharmaceutical composition or kit of parts of the invention.

The invention further provides the use of the combination,pharmaceutical composition or kit of parts of the invention for themanufacture of a medicament for treating and/or preventing cancer.

The invention also provides for a method for delaying in patient theonset of cancer comprising the administration of a pharmaceuticallyeffective amount of the combination, pharmaceutical composition or kitof parts of the invention to a patient in need thereof Various cancersare known in the art. Cancers that can be treated using the methods ofthe invention include solid cancers and non-solid cancers, especiallybenign and malignant solid tumors and benign and malignant non-solidtumors. The cancer may be metastatic or non-metastatic. The cancer maybe may be familial or sporadic.

In one embodiment, the cancer to be treated according to the presentinvention is a solid cancer. As used herein, the term “solid cancer”encompasses any cancer (also referred to as malignancy) that forms adiscrete tumor mass, as opposed to cancers (or malignancies) thatdiffusely infiltrate a tissue without forming a mass.

Examples of solid tumors include, but are not limited to: biliary tractcancer, brain cancer (including glioblastomas and medulloblastomas),breast cancer, carcinoid, cervical cancer, choriocarcinoma, coloncancer, colorectal cancer, endometrial cancer, esophageal cancer,gastric cancer, glioma, head and neck cancer, intraepithelial neoplasms(including Bowen's disease and Paget's disease), liver cancer, lungcancer, neuroblastomas, oral cancer (including squamous cell carcinoma),ovarian cancer (including those arising from epithelial cells, stromalcells, germ cells and mesenchymal cells), pancreatic cancer, prostatecancer, rectal cancer, renal cancer (including adenocarcinoma and Wilmstumor), sarcomas (including leiomyosarcoma, rhabdomyosarcoma,liposarcoma, fibrosarcoma and osteosarcoma), skin cancer (includingmelanoma, Kaposi's sarcoma, basocellular cancer and squamous cellcancer), testicular cancer including germinal tumors (seminomas, andnon-seminomas such as teratomas and choriocarcinomas), stromal tumors,germ cell tumors, thyroid cancer (including thyroid adenocarcinoma andmedullary carcinoma) and urothelial cancer.

In another embodiment, the cancer to be treated according to the presentinvention is a non-solid cancer. Examples of non-solid tumors includebut are not limited to hematological neoplasms. As used herein, ahematologic neoplasm is a term of art which includes lymphoid disorders,myeloid disorders, and AIDS associated leukemias.

Lymphoid disorders include but are not limited to acute lymphocyticleukemia and chronic lymphoproliferative disorders (e.g., lymphomas,myelomas, and chronic lymphoid leukemias). Lymphomas include, forexample, Hodgkin's disease, non-Hodgkin's lymphoma lymphomas, andlymphocytic lymphomas). Chronic lymphoid leukemias include, for example,T cell chronic lymphoid leukemias and B cell chronic lymphoid leukemias.

In a specific embodiment, the cancer is selected from breast, carcinoid,cervical, colorectal, endometrial, glioma, head and neck, liver, lung,melanoma, ovarian, pancreatic, prostate, renal, gastric, thyroid andurothelial cancers.

In a specific embodiment, the cancer is breast cancer. In a specificembodiment, the cancer is carcinoid cancer. In a specific embodiment,the cancer is cervical cancer. In a specific embodiment, the cancer iscolorectal cancer. In a specific embodiment, the cancer is endometrialcancer. In a specific embodiment, the cancer is glioma. In a specificembodiment, the cancer is head and neck cancer. In a specificembodiment, the cancer is liver cancer. In a specific embodiment, thecancer is lung cancer. In a specific embodiment, the cancer is melanoma.In a specific embodiment, the cancer is ovarian cancer. In a specificembodiment, the cancer is pancreatic cancer. In a specific embodiment,the cancer is prostate cancer. In a specific embodiment, the cancer isrenal cancer. In a specific embodiment, the cancer is gastric cancer. Ina specific embodiment, the cancer is thyroid cancer. In a specificembodiment, the cancer is urothelial cancer.

In another specific embodiment, the cancer is selected from the groupconsisting of leukemia and multiple myeloma.

In one embodiment, the invention relates to the combination,pharmaceutical composition or kit of parts as herein above defined foruse in immunotherapy, preferable as cancer immunotherapy.

In one embodiment, the invention relates to a method of immunotherapy,preferably of cancer immunotherapy, which comprises administering to amammal species in need thereof a therapeutically effective amount of thecombination, pharmaceutical composition or kit of parts of theinvention.

The invention further provides the use of the combination,pharmaceutical composition or kit of parts of the invention for themanufacture of a medicament for conducting immunotherapy, preferably ofcancer immunotherapy.

In one embodiment, the invention relates to the use of the combination,pharmaceutical composition or kit of parts of the invention, forincreasing immune recognition and destruction of the cancer cells.

In one embodiment, the invention relates to a method for increasingimmune recognition and destruction of the cancer cells, which comprisesadministering to a mammal species in need thereof a therapeuticallyeffective amount of the combination, pharmaceutical composition or kitof parts of the invention.

The invention further provides the use of the combination,pharmaceutical composition or kit of parts of the invention for themanufacture of a medicament for increasing immune recognition anddestruction of the cancer cells.

Preferably, the patient is a warm-blooded animal, more preferably ahuman.

In one embodiment, the patient receiving the A2AR inhibitor as hereindescribed is also receiving an immunotherapy, a chemotherapy,radiotherapy or a combination thereof.

In one embodiment, the subject is resistant to an immunotherapy. In oneembodiment, the subject is resistant to a cancer immunotherapy.

In one embodiment, the subject is resistant to a chemotherapy. In oneembodiment, the subject is resistant to a cancer chemotherapy.

In one embodiment, the subject is resistant to a radiotherapy. In oneembodiment, the subject is resistant to a cancer radiotherapy.

The invention also relates to a compound of Formula (I) as defined abovefor use in therapy in combination with an anticancer agent as definedabove, especially immunotherapeutic agents, chemotherapeutic agents,antiangiogenic agents, multidrug resistance-associated proteinsinhibitors, radiotherapeutic agents, or any combination thereof.

The invention also relates to a compound of Formula (I) as defined abovefor use in a patient treated by immunotherapy, a chemotherapy,radiotherapy or a combination thereof.

The invention thus also relates to a method for treating cancer in asubject resistant to an anticancer agent, comprising administering tothe patient a compound of Formula (I) as defined above and saidanticancer agent. In one embodiment, said anticancer agent is animmunotherapy, a chemotherapy, radiotherapy or a combination thereof.

The invention further relates to a method for increasing the therapeuticresponse of a subject to an anticancer agent, comprising furtheradministering to the patient a compound of Formula (I) as defined above.In one embodiment, said anticancer agent is an immunotherapy, achemotherapy, radiotherapy or a combination thereof.

The invention also relates to an anticancer agent as defined above foruse in therapy in combination with a compound of Formula (I) as definedabove.

BRIEF DESCRIPTION OF THE DRAWINGS

FIGS. 1A and 1B show the anti-tumor efficacy of A2AR inhibitor Compound7 administered as single agent in liver Hepa 1-6 syngeneic tumor model.FIG. 1A is a graph representing the tumor volume over time afterinoculation. FIG. 1B shows the distribution of tumors volume at day 22.

FIGS. 2A and 2B show the A20 tumor growth upon treatment with Compound 7used as single agent or in combination with anti-PD-L1. FIG. 2A is agraph representing the tumor volume over time after inoculation. FIG. 2Bshows the distribution of tumors volume at day 23.

FIGS. 3A-E show EMT6 tumor growth upon treatment with Compound 8a incombination with antagonist anti-CTLA4 mAb. The number of completeresponders (CR) out of 10 mice per group is indicated. Tumor growth overtime: Median (FIG. 3A), Vehicle (FIG. 3B) and aCTLA-4, 3 mg/kg Q3Dx2(day 9, 12) standalone (FIG. 3C) or in combination with D) Compound 8,0.1 mg/kg QDx25 (FIG. 3D) or Compound 8, 0.6 mg/kg QDx25 (FIG. 3E).

FIGS. 4A and 4B show that A2AR inhibitor Compound 8a in combination withanti-PD-L1 mAb modulates T cell infiltrate in the A20 tumormicroenvironment. The absolute quantification of the number of CD3+ Tcells (FIG. 4A) and CD8+ T cells (FIG. 4B) was measured by calculationfrom the average of 10 high powered fields/sections (10 HPF) fromindependent tumors (symbols represent individual mice; n=5 to 7 miceper/group). The median and interquartile range are shown, p values wherecalculated using Mann Whitney non-parametric t test.

FIGS. 5A-5E show the MCA205 tumor growth upon treatment with Compound 8bused as single agent or in combination with Oxaliplatin. FIG. 5A is agraph representing the median tumor volume over time after subcutaneousinoculation of tumor cells. FIGS. 5B-E are the individual tumor growthvolumes of mice treated with Vehicle (FIG. 5B), Compound 8b at 0.6 mg/kgQDx25 (FIG. 5C), and Oxaliplatin at 10 mg/kg QDx1 (day 11) in standalone(FIG. 5D) or in combination with Compound 8b at 0.6 mg/kg QDx25 (FIG.5E).

FIGS. 6A-G show the CT26 tumor growth upon treatment with Compound 8b at0.6 mg/kg QDx32, anti-TIGIT mAb at 1 mg/kg Q3Dx3 (day 9, 12 and 15),Doxorubicin 6 mg/kg Q3Dx2 (day 10 and 14), and various combinationsthereof. FIG. 6A is a graph representing the median tumor volume overtime after subcutaneous inoculation of tumor cells. FIGS. 6B-D are theindividual tumor growth volumes of mice treated with Vehicle (FIG. 6B),Doxorubicin (FIG. 6C) or anti-TIGIT mAb (FIG. 6D). FIGS. 6E-G are theindividual tumor growth volumes of mice treated with a combination ofDoxorubicin and anti-TIGIT (FIG. 6E), Compound 8b and Doxorubicin (FIG.6F) and triple combination of Compound 8b, Doxorubicin and anti-TIGIT(FIG. 6G).

FIG. 7A shows the proportion of proliferating CD4⁺ cells as determinedby CFSE dilution. FIG. 7B shows the concentration of TNFα present in thecell culture supernatants. CD39i denotes the combination of the CD39inhibitors ARL67156 and POM-1. Dark grey bars show Compound 8a treatedwells, whilst light grey bars denote concentration-matched DMSO treatedwells. Results are shown as mean value from duplicate wells±standarddeviation.

EXAMPLES

The present invention will be better understood with reference to thefollowing examples.

These examples are intended to representative of specific embodiments ofthe invention, and are not intended as limiting the scope of theinvention.

The following abbreviations are used:

BHT: butylated hydroxytoluene

BID: bis in die (i.e. twice a day)

ca.: circa

CR: complete responder

DMSO: dimethylsulfoxide

EDTA: ethylenediaminetetraacetic acid

HPLC: high-performance liquid chromatography

LC-MS: liquid chromatography-mass spectrometry

mAb: monoclonal antibody

mg: milligram

MS: mass spectrometry

PBS: phosphate buffered saline

PEG: polyethylene glycol

QD: quaque die (i.e. once a day)

Q3D: quaque 3 die (i.e. every 3 days)

rpm: revolutions per minutes

TGL: tumor growth inhibition

TILs: tumor infiltrating lymphocytes

UV: ultraviolet

μL: microliter

% v/v: percentage in volume to the total volume of the composition

% w/w: percentage in weight to the total weight of the composition

I. Compounds

The compounds of Formula (I) are prepared as described inPCT/EP2018/058301.

II. Pharmaceutical Compositions

II.1. Manufacturing of Pharmaceutical Compositions

Two composition according to the invention were prepared under capsulesform, comprising the following ingredients (Table 2):

TABLE 2 Capsules compositions (% w/w). Components 1 2A 3 4 5 6 7 8Compound 8a 10 10 10 Compound 8a esylate salt 10 10 10 10 Compound 8aHCl salt 10 Gelucire ® 44/14 71.9 80.9 71.9 89 90 Vitamin E TPGS 71 7171 PEG 400 18 \ 18 PEG 3350 18 18 18 Caprylic acid \ 9 Butylated 0.1 0.10.1 hydroxytoluene (BHT) polyvinyl caprolactam- 1.0 1.0 1.0 polyvinylacetate-polyethylene glycol graft copolymer Hydroxypropylmethylcellulose1.0

Capsules 2A were prepared from a common blend using conventional mixingand capsule filling processes according to Good Manufacturing Practice.Lauroyl polyoxyl-32 glycerides is melted with a product temperature notless than 50° C. but not exceeding 80° C. Caprylic acid and thenbutylated hydroxytoluene (BHT) are then added to the lauroyl polyoxyl-32glycerides and mixed together using a suitable mixer. Compound 8a isthen added gradually to the lauroyl polyoxyl-32 glycerides/caprylicacid/BHT mixture being continuously mixed together using a suitablemixer to produce a visually uniform distribution of the drug substancewith no observable lumps or agglomerates. Mixing is then continued forat least 30 minutes to ensure that the drug substance is homogeneouslydistributed as determined visually. The blend is then maintained in themolten state with continued mixing and is filled into appropriatelysized gelatine capsule shells to the target capsule fill weight. Capsulefilling is undertaken using conventional capsule filling methods andequipment suitable for use with molten semi-solid formulations.

A similar process was carried out for manufacturing all other capsuleexamples, with Vitamin E TPGS being substituted for lauroyl polyoxyl-32glycerides. Polyvinyl caprolactam-polyvinyl acetate-polyethylene glycolgraft copolymer and hydroxypropylmethylcellulose are added to the moltenlauroyl polyoxyl-32 glycerides or Vitamin TPGS as required.

II.2. Pharmacology Examples

II.2.i. Thermodynamic Solubility by Shake Flask—HPLC

This example aims at showing that the compounds of Formula (I) arepoorly soluble in water or in aqueous buffers and thus that there is aneed to provide a formulation of said compounds.

Compound 8a (2.0 mg, crystalline solid) was weighed into the lowerchambers of Whatman miniuniprep vials. 450 μL of tested medium was addedinto each chamber. After this addition, filter pistons of miniuniprepvials were placed and compressed to the position of the liquid level toallow for contact of the medium and compound with the filter duringincubation. The samples were vortexed for 2 minutes, then incubation wascarried out at room temperature (ca. 22˜25° C.) for 24 hours withshaking at 880 rpm.

The miniunipreps were compressed to prepare the filtrates for injectioninto HPLC system. The supernatants were diluted with the medium by afactor of 50 folds to make diluents. Three UV standard solutions wereinjected into IPLC from low to high concentration, followed by testingof the diluents and supernatants. Testing samples were injected induplicate.

The results are shown in Table 3:

TABLE 3 Solubility of Compound 8a in tested aqueous media. Thermodynamicsolubility of Tested medium Compound 8a (μg/mL) water <0.6 pH 7.4 2FaSSIF 1-10

In all tested aqueous media, the solubility is very low and the test inFaSSIF (Fasted-State Simulated Intestinal Fluid) is representative of alow intestinal solubility.

II.2.ii. Exposures in Dogs after Oral Dosing

The purpose of this assay is to determine the exposure in dogs afteroral dosing with the pharmaceutical composition of the invention. Dogsare administered with pentagastrin just before administration of thecapsules formulations in order to stimulate the secretion of gastricacid.

Five male Beagle dogs (>6 months of age, 7-9 kg of weight) were fed theafternoon (at 3:30 to 4:00 pm) prior to the day of oral dosing and theremaining food was removed at about 7:00 pm. Food was withheld untilafter the 4-hour blood collection.

Pentagastrin (Sigma, 1 mg) was dissolved in 200 μL (0.200 mL) of asolution of 10% (v/v) ammonium hydroxide (NH₄OH)/90% (v/v) PhosphateBuffered Saline (PBS). 0.12 mL of this stock solution was then dilutedby adding 4.88 mL of PBS solution, then the vial was vortexed. Thesolution was filtered (under a laminar flow hood) through a 0.22 msyringe filter into a sterile amber glass serum bottle. Animals wereadministered with Pentagastrin at 6 μg/kg by intramuscular injection atapproximately 30 minutes (±2 min) before dosing with the capsules.

The dose capsule formulations (80 mg/dog, i.e. about 10 mg/kg of animal)were administered by placing the capsules in the far back of the dog'sthroat, then pushing it past the pharynx using a thumb or index finger.The capsules were moistened with water to facilitate dosing. Afteradministering the dose, swallowing was induced, if needed, by gentlystroking the dog's throat or tapping the dog under the chin. Immediatelyfollowing capsule administration, water (4 mL/kg) or an aqueous HClsolution at pH 2.5 (4 mL/kg) was given to the mouth to the animals tohelp capsule swallowing. After administration, the animals' mouths wereinspected to ensure that the dose had been swallowed.

Blood was collected at the timepoints indicated in Table 4 into a tube(Jiangsu Kangjian medical supplies co., LTD) containing Potassium (K2)EDTA*2H₂O (0.85-1.15 mg) on wet ice and processed for plasma bycentrifugation (3,000×g for 10 minutes at 2 to 8° C.) within one hour ofcollection. The plasma samples (0.2 mL) were transferred into labeledpolypropylene micro-centrifuge tubes and stored frozen at −60° C. orlower until bio-analysis.

Concentrations of Compound 8a in plasma were quantified by LC-MS/MS. Theconcentrations measured (mean of five dogs) are indicated in Table 4,while the main pharmacokinetic parameters are indicated in Table 5.

TABLE 4 Concentration of Compound 8a in plasma. Timepoint Formulation 1Formulation 2A (h) Concentration (ng/mL) Concentration (ng/mL) 0.25 94.794.4 0.50 431 292 1.0 242 384 2.0 161 108 4.0 9.91 10.5 8.0 3.42 3.45 124.68 <1

TABLE 5 Pharmacokinetic parameters. Formulation 1 Formulation 2A Dose(mg/dog) 80 80 (active ingredient) Additional liquid Water Aqueous HClpH 2.5 C_(max) (ng/mL) 481 674 T_(max) (h) 0.9 1 AUC_(last) (h*ng/mL)554 1818 AUC_(inf) (h*ng/mL) 561 1823 C_(max): maximum plasmaconcentration of the active ingredient obtained after administration;T_(max): time to reach C_(max); AUC: area under the curve, correspondingto the integral of the concentration-time curve (AUC_(last): AUC up tothe last sample drawn; AUC_(inf): AUC up to infinite time)

Above results clearly evidence that the use of the pharmaceuticalcomposition of the invention enables suitable oral bioavailability ofthe thiocarbamates A2A inhibitors.

III. Combinations with Anticancer Agents—In Vivo Studies

Summary of the Results:

Compound 7 at 3 mg/kg BID, significantly delayed growth of HEPA-1-6tumors compared to vehicle control in syngeneic host.

In combination with anti-PD-L1, Compound 7 demonstrated anti-tumoractivity at 0.3 mg/kg BID and, at 3 mg/kg BID, significantly delayingtumor growth versus anti-PD-L1 control in a A20 syngeneic mouse lymphomamodel.

In combination with anti-CTLA-4, Compound 8a demonstrated antitumoractivity at 0.1 mg/kg and starting at 0.6 mg/kg significantly delayedtumor growth in a dose dependent manner in the EMT6 syngeneic mousebreast cancer model. In addition, in cured mice, prevented growth afterre-inoculation suggesting induction of a specific memory response.

Further illustrating the mechanism of action, in combination withanti-PD-L1, Compound 8a at 3 mg/kg BID significantly increased CD3+ andCD8+ cell infiltrations without an effect of FOXP3 expressing cells.

In combination with Oxaliplatin, Compound 8b demonstrated significantantitumor activity at 0.6 mg/kg by delaying tumor growth in the MCA205syngeneic mouse fibrosarcoma cancer model.

In combination with Doxorubicin, Compound 8b demonstrated significantantitumor activity at 0.6 mg/kg by delaying tumor growth in the CT26syngeneic mouse colon cancer model. In the same example a triplecombination of Doxorubicin, anti-TIGIT mAb at 1 mg/kg and Compound 8b at0.6 mg/kg demonstrated significantly enhanced antitumor activitycompared to double combinations of Doxorubicin and Compound 8b orDoxorubicin and anti-TIGIT mAb in the CT26 syngeneic mouse colon cancermodel.

III.1. Syngeneic HEPA1-6 Mouse Liver Tumor Model

This study evaluated the anti-tumor activity of Compound 7 in a mousehepatoma model (NCR-A2A-032).

C57BL/6 female mice (8 weeks old) were inoculated subcutaneously in theright flank region with Hepa 1-6 tumor cells (on day 0). When tumor sizereached about 50 mm³ (on Day 4), mice were randomly allocated intoexperimental groups and treatment was initiated from day 4 to 25. Micewere administered vehicle p.o. (10% DMSO, 10% Solutol HS15 in dH₂O pH3)or Compound 7 at 0.3 and 3 mg/kg, p.o., BIDx 21.

At 3 mg/kg, Compound 7 demonstrated significant antitumor efficacy witha tumor growth inhibition (TGI) of 44% calculated on Day 22 (p=0.024).(FIGS. 1A and 1B).

III.2. Syngeneic A20 Experimental Lymphoma Model in Combination withAnti-PD-L1

In this study the anti-tumor efficacy of Compound 7 was assessed eitheras single agent (monotherapy) or in combination with antagonistanti-Programmed Death-Ligand 1 (anti-PD-L1) monoclonal antibody (1°F.9G2, BioXcell) in a model of B cell lymphoma model. (NCR-A2A-031).

BALB/c female mice (8 weeks old) were inoculated with A20 mouse B-celltumor cells, subcutaneously in the right lower flank region (day 0).When tumors reached a size of about 50 mm³ (Day 7), mice were allocatedrandomly into groups and treatment was initiated. Mice were administeredvehicle p.o. (10% DMSO, 10% Solutol HS15 in dH₂O pH3) as control orCompound 7 at 0.3 and 3 mg/kg, p.o., BIDx 21 (Day 7 to 28) or anti-PD-L1mAb at 5 mg/kg i.p., Q3Dx3 (day 9, 12, 15) as single agent or incombination.

Compound 7 administered p.o. at 0.3 mg/kg, BID, in combination withanti-PD-L1 mAb, demonstrated anti-tumor activity (TGI=76%, determined onday 23) although not reaching statistical significance (p=0.106)compared with anti-PD-L1 single therapy (TGI=49%).

Compound 7 administered at 3 mg/kg BID in combination with anti-PD-L1mAb, showed significant enhancement of antitumor activity (p=0.039 forTGI and p=0.0008 for overall suppression of tumor growth) compared withsingle agent anti-PD-L1 mAb (TGI=82 and 49%, observed on day 23,respectively) (FIGS. 2A and 2B).

Statistical analysis also revealed that Compound 7 synergises withanti-PD-L1 mAb to significantly inhibit the growth of established A20syngeneic tumor (p=0.017).

III.3. Syngeneic EMT6 Breast Cancer Model in Combination withAnti-CTLA-4

The anti-tumor efficacy of Compound 8a was assessed in combination withanti-cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) antagonist mAb(9H10, BioXcell) in a model of triple negative mammary cancer.

EMT6 mammary tumor cells were inoculated orthotopically into the lowerright mammary fat pad of 8 week old female BALB/c mice (day 0). Whentumors reached a size of about 60 mm³ (day 9), mice were randomlyallocated into groups. Mice were administered with control vehicle p.o.(10% DMSO, 10% Solutol HS15 in dH₂O pH3) or anti-CTLA-4 mAb at 3 mg/kgi.p., Q3Dx2 (day 9, 12) stand alone or in combination with Compound 8aat 0.1 mg/kg p.o. QDx25 or 0.6 mg/kg p.o. QDx25.

Compound 8a combined with anti-CTLA-4 significantly reduced tumor growthwhen administered at 0.6 mg/kg (p=0.0153, mean TGI=99% determined on day31—complete responder (CR)=7/10) vs. anti-CTLA4 alone (CR=3, meanTGI=72%, determined on day 31) (FIGS. 3A, 3B, 3C and 3E). AlthoughCompound 8a at 0.1 mg/kg in combination with anti-CTLA-4 mAb (as above)did not reach statistical significance (p=0.8665) vs. anti-CTLA4 mAb assingle agent, it resulted in CR=5 (n=10 mice group) and mean TGI=85%(FIGS. 3A and 3D). In addition, there was also no statisticallysignificant difference between doses. This suggests that Compound 8aalready demonstrates in vivo activity starting at 0.1 mg/kg incombination with anti-CTLA4 mAb (FIGS. 1A and 1 ).

When complete responders (cure mice) re-challenged with EMT6 tumor cells(specific antigen) or unrelated colon CT26 cells (non-specific antigen),the mice previously treated with Compound 8a at 0.1 and 0.6 mg/kg incombination with anti-CTLA-4 mAb, were not protected against thechallenge of unrelated CT26 cells (100% of tumor incidence) but fullyrejected EMT6 cells (no tumor formation) in 66% (0.1 mg/kg) and 100%(0.6 mg/kg) of mice respectively.

Compound 8a therefore significantly inhibited the growth of establishedEMT6 syngeneic tumors in combination with anti-CTLA-4 antagonist mAb andinduce long-term memory response that results in durable specificantitumor response.

III.4. Mechanism of Action of Compound 8A to Reduce Tumor Growth in A20Lymphoma Model

Having established that Compound 8a (or its racemate mixture, Compound7) demonstrates anti-tumor activity in several experimental tumor modelsat well-tolerated doses, this study evaluated the mechanism of actionresponsible for this effect.

Compound 8a was evaluated in B cell Lymphoma tumor model, as singleagent and in combination with antagonist anti-PD-L1 mAb. A20tumor-bearing mice (tumor size of about 70 mm³, day 12 afterinoculation) were treated with control vehicle p.o. (10% DMSO, 10%Solutol HS15 in dH₂O pH3) or anti-PD-L1 mAb at 1 mg/kg i.p., Q3Dx3 (day14, 17 and 20) and Compound 8a 3 mg/kg p.o., BIDx10 as single agent orin combination with anti-PD-L1 mAb. By IHC staining, thetumor-infiltrating lymphocytes (TIL), including total CD3⁺ T cells, CD8⁺T cells and FOXP3⁺ Treg cells, were characterized and compared using asemi-quantitative technique.

Compound 8a at 3 mg/kg as single agent regimen had a moderate effect onCD3⁺ and CD8⁺ TILs in the tumor environment but the increase ininfiltrate did not reach significance. The combination of Compound 8a at3 mg/kg with anti-PDL-1 mAb demonstrated a significant increase in CD3⁺T cells (p=0.0068) and CD8⁺ T cell (p=0.0035) infiltration in tumor ascompared to anti-PDL-1 mAb used as single agent (FIGS. 4A and 4B). Nostatistically significant change in Treg infiltrate was demonstratedwith any treatment in single agent or combination.

These results strongly suggest that Compound 8a in combination withaPDL-1 mAb significantly modulates the immunosuppressive nature of thetumor microenvironment by increasing TILs infiltration.

III.5. Syngeneic MCA205 Experimental Fibrosarcoma Model in Combinationwith Oxaliplatin

The anti-tumor efficacy of Compound 8b was assessed in combination withOxaliplatin, in an established murine syngeneic MCA205 fibrosarcomatumor model.

MCA205 tumor cells were inoculated subcutaneously into the right flankof C57BL/6 mice. When tumors reached an average size of about 80 mm³,mice were randomly allocated into groups. Mice were administered vehiclep.o. (10% DMSO, 10% Solutol HS15 in dH₂O pH3) as control or Compound 8bat 0.6 mg/kg QDx25 (day 11-36) or Oxaliplatin at 10 mg/kg i.p. QDx1 (day11) as single agent or in combination.

Oxaliplatin, given as a single administration i.p. at D11, demonstrateda significant delay in tumor growth (p=0.0202) compared to the Vehicle(FIGS. 5A, 5B, and 5D).

Compound 8b, administered p.o. at 0.6 mg/kg once daily (QD) for 25consecutive days in combination with Oxaliplatin, demonstratedsignificant tumor growth delay compared to Vehicle (p<0.0001) and alsosignificant tumor growth delay when compared to Oxaliplatin monotherapy(p=0.0284) (FIGS. 5A-E).

III.6. Syngeneic CT26 Experimental Colon Cancer Model in Combinationwith Doxorubicin and/or Anti-TIGIT Mab

In this study the anti-tumor efficacy of Compound 8b was assessed incombination with chemotherapeutic agent, Doxorubicin and with anti-TIGITmAb in a Colon tumor model (CT26).

BALB/c female mice (8 weeks old) were inoculated with CT26 mouse tumorcells, subcutaneously in the right lower flank region (day 0). Whentumors reached a size of about 90 mm³ (Day 9), mice were allocatedrandomly into groups and treatment was initiated. Mice were administeredvehicle p.o. (10% DMSO, 10% Solutol HS15 in dH₂O pH3) as control orDoxorubicin at 6 mg/kg i.v., Q4Dx2 (day 10 and 14) or anti-TIGIT mAb,29527 (see U.S. Ser. No. 10/329,349) at 1 mg/kg i.p. Q3Dx3 (day 9, 12and 15), as single agent or in combinations with Compound 8b at 0.6mg/kg, p.o., QDx 32 (Day 9 to 41).

Intraperitoneal injection of 1 mg/kg of anti-TIGIT mAb, 29527 (see U.S.Ser. No. 10/329,349) at days 9, 12 and 15 after tumor cell inoculation,significantly suppressed tumor growth compared to mice treated withvehicle (p=0.0009, FIGS. 6A and 6B)

Doxorubicin, administered twice at 6 mg/kg on day 10 and 14, had nosignificant effect on tumor growth (p=0.14, FIGS. 6A and 6C), whilecombination with anti-TIGIT mAb improved anti-tumor efficacy (p=0.008and p=0.0002 respectively, when compared to anti-TIGIT mAb orDoxorubicin stand-alone therapy (FIGS. 6A, 6C, 6D, and 6E).

Compound 8b administered at 0.6 mg/kg QD from day 9 in combination withDoxorubicin given at 6 mg/kg on day 10 and 14 achieved significantanti-tumor effect when compared to stand alone administration ofDoxorubicin (p=0.0003, FIGS. 6A, 6C, and 6F). The anti-tumor growthefficacy in mice treated with a triple combination of Compound 8b,Doxorubicin and anti-TIGIT, was significantly higher when compared toDoxorubicin+Compound 8b (p<0.0001) or when compared toanti-TIGIT+Doxorubicin (p=0.003), and resulted in 5 complete responders(CR) out of 8 mice in this triple combination treated group verses zeroand one CR out of 10 mice in the Doxorubicin+Compound 8b andanti-TIGIT+Doxorubicin combinations respectively. (FIGS. 6A, 6E, 6F, and6G).

III.7. Restoration of Human T Cells Function by a Combination with CD39Inhibitors

Purpose. When T cells are activated, they proliferate and producepro-inflammatory cytokines. Addition of adenosine triphosphate (ATP) tothe culture provides a source of adenosine as ATP is first converted toadenosine monophosphate by CD39 and then to adenosine by CD73. Adenosinesuppresses T cell proliferation and cytokine production in part byengaging the A2A receptor. The present assay thus aims to show that theinhibition of proliferation and inflammatory cytokine production by Tcells in the presence of ATP may be reversed by a combination of the A2Areceptor antagonist Compound 8a and the CD39 inhibitors ARL67156 andPOM-1.

PBMC and CD3⁺ T cell isolation. Venous blood from healthy volunteers wasobtained via ImmuneHealth (Centre Hospitalier Universitaire Tivoli, LaLouviere, Belgium). Peripheral blood mononuclear cells (PBMCs) werecollected by density gradient centrifugation, using SepMate-50 tubes(StemCell Technologies, Grenoble, France) and Lymphoprep (Axis-shield,Oslo, Norway) according to the manufacturer's instructions. PBMCs werestored in heat inactivated foetal bovine serum (hiFBS; Gibco,ThermoFisher Scientific, Merelbeke, Belgium) containing 10% DMSO inliquid nitrogen until required. PBMCs were thawed and washed into PBS(with 10% hiFBS) and labelled with 1 μM CFSE (Life Technologies) at roomtemperature for 5 minutes. Cells were washed into StemCell isolationbuffer and CD3⁺ T cells were isolated by immunomagnetic negativeselection, using the EasySep Human T Cell Isolation Kit (StemCellTechnologies) as per manufacturer's instructions.

Human T cell activation assay. Human CD3⁺ T cells were washed intoX-VIVO15 medium (LONZA) and distributed into a 96 round well plate at8×10⁴ cells per well. Wells received either the A2A receptor antagonistcompound 8a at a final concentration of 100 nM or a matchedconcentration of DMSO (Sigma-Aldrich). In addition, some wells receiveda combination of the CD39 inhibitors ARL67156 (Tocris Bioscience, 100μM) and POM-1 (Tocris Bioscience, 10 μM), or a combination of both CD39inhibitors and compound 8a. Cells were cultured in the presence orabsence of ATP (Sigma-Aldrich) at a final concentration of 100 μM andwere activated by adding anti-CD3 and anti-CD28 coated microbeads(Dynabeads human T-activator CD3/CD28; Life Technologies).

Cells were placed in a 37° C. humidified tissue culture incubator with5% CO₂ for 72 hours. After 72 hours, supernatants were sampled andstored at −20° C. Proliferation of CD4⁺ T cells was assessed bydetermining CFSE dilution by flow cytometry using a BD LSRFortessa (BDBiosciences). Supernatants were later thawed and TNFα was quantifiedusing the AlphaLISA Human TNFα Biotin-Free Detection Kit (AL325;Perkin-Elmer, Zaventem, Belgium), according to the manufacturer'sinstructions.

Results. The presence of ATP significantly inhibited CD4⁺ T cellproliferation which was almost completely rescued by the CD39 inhibitorsARL67156 and POM-1 (FIG. 7A). The presence of compound 8a made a smallfurther contribution to increasing proliferation of these cells. ATPalso significantly inhibited the production of TNFα. Both compound 8aand the CD39 inhibitors individually could restore approximately 50% ofTNFα production, with a combination resulting in complete rescue (FIG.7B). Overall, these data illustrate the value of combining compound 8awith a CD39 inhibitor for cancer immunotherapy, aiming at fullrestoration of T cell function in the ATP-rich tumor microenvironment.

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 9. A method of treating cancer ina patient in need thereof, the method comprising administering to thepatient a therapeutically acceptable effective amount of a combinationcomprising: (a) a compound of Formula (I):

or a pharmaceutically acceptable salt thereof, wherein: R¹ represents 5-or 6-membered heteroaryl or 5- or 6-membered aryl, wherein heteroaryl oraryl groups are optionally substituted by one or more substituentselected from C₁-C₆ alkyl and halo; R² represents 6-membered aryl or6-membered heteroaryl, wherein heteroaryl or aryl groups are optionallysubstituted by one or more substituent selected from halo, alkyl,heterocyclyl, alkoxy, cycloalkyloxy, heterocyclyloxy, carbonyl,alkylcarbonyl, aminocarbonyl, hydroxycarbonyl, heterocyclylcarbonyl,alkylsulfoxide, alkylsulfonyl, aminosulfonyl, heterocyclylsulfonyl,alkylsulfonimidoyl, carbonylamino, sulfonylamino and alkylsulfonealkyl;said substituents being optionally substituted by one or moresubstituent selected from oxo, halo, hydroxy, cyano, alkyl, alkenyl,aldehyde, heterocyclylalkyl, hydroxyalkyl, dihydroxyalkyl,hydroxyalkylaminoalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl,(heterocyclyl)(alkyl)aminoalkyl, heterocyclyl, heteroaryl,alkylheteroaryl, alkyne, alkoxy, amino, dialkylamino,aminoalkylcarbonylamino, aminocarbonylalkylamino,(aminocarbonylalkyl)(alkyl)amino, alkenylcarbonylamino, hydroxycarbonyl,alkyloxycarbonyl, aminocarbonyl, aminoalkylaminocarbonyl,alkylaminoalkylaminocarbonyl, dialkylaminoalkylaminocarbonyl,heterocyclylalkylaminocarbonyl, (alkylaminoalkyl)(alkyl)aminocarbonyl,alkylaminoalkylcarbonyl, dialkylaminoalkylcarbonyl,heterocyclylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, alkylsulfoxide,alkylsulfoxidealkyl alkylsulfonyl and alkylsulfonealkyl; or theheteroaryl or aryl groups are optionally substituted with twosubstituents that form together with the atoms to which they areattached a 5- or 6-membered aryl ring, a 5- or 6-membered heteroarylring, a 5- or 6-membered cycloalkyl ring or a 5- or 6-memberedheterocyclyl ring; optionally substituted by one or more substituentselected from oxo, halo, hydroxy, cyano, alkyl, alkenyl, aldehyde,heterocyclylalkyl, hydroxyalkyl, dihydroxyalkyl, hydroxyalkylaminoalkyl,aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl,(heterocyclyl)(alkyl)aminoalkyl, heterocyclyl, heteroaryl,alkylheteroaryl, alkyne, alkoxy, amino, dialkylamino,aminoalkylcarbonylamino, aminocarbonylalkylamino,(aminocarbonylalkyl)(alkyl)amino, alkenylcarbonylamino, hydroxycarbonyl,alkyloxycarbonyl, aminocarbonyl, aminoalkylaminocarbonyl,alkylaminoalkylaminocarbonyl, dialkylaminoalkylaminocarbonyl,heterocyclylalkylaminocarbonyl, (alkylaminoalkyl)(alkyl)aminocarbonyl,alkylaminoalkylcarbonyl, dialkylaminoalkylcarbonyl,heterocyclylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, alkylsulfoxide,alkylsulfoxidealkyl, alkylsulfonyl and alkylsulfonealkyl; and (b) acheckpoint inhibitor selected from the group consisting of a PD-1antibody and a PD-L1 antibody.
 10. The method according to claim 9,wherein the compound is of Formula (Ia)

or a pharmaceutically acceptable salt thereof, wherein: R¹ represents 5-or 6-membered heteroaryl or 5- or 6-membered aryl, wherein heteroaryl oraryl groups are optionally substituted by one or more substituentselected from C₁-C₆ alkyl and halo; X¹ and X² are each independentlyselected from C and N; R^(1′) is absent when X¹ is N; or when X¹ is C,R^(1′) represents H, halo, alkyl, heterocyclyl, alkoxy, cycloalkyloxy,heterocyclyloxy, carbonyl, alkylcarbonyl, aminocarbonyl,hydroxycarbonyl, heterocyclylcarbonyl, alkylsulfoxide, alkylsulfonyl,aminosulfonyl, heterocyclylsulfonyl, alkylsulfonimidoyl, carbonylamino,sulfonylamino or alkylsulfonealkyl; said substituents being optionallysubstituted by one or more substituent selected from oxo, halo, hydroxy,cyano, alkyl, alkenyl, aldehyde, heterocyclylalkyl, hydroxyalkyl,dihydroxyalkyl, hydroxyalkylaminoalkyl, aminoalkyl, alkylaminoalkyl,dialkylaminoalkyl, (heterocyclyl)(alkyl)aminoalkyl, heterocyclyl,heteroaryl, alkylheteroaryl, alkyne, alkoxy, amino, dialkylamino,aminoalkylcarbonylamino, aminocarbonylalkylamino,(aminocarbonylalkyl)(alkyl)amino, alkenylcarbonylamino, hydroxycarbonyl,alkyloxycarbonyl, aminocarbonyl, aminoalkylaminocarbonyl,alkylaminoalkylaminocarbonyl, dialkylaminoalkylaminocarbonyl,heterocyclylalkylaminocarbonyl, (alkylaminoalkyl)(alkyl)aminocarbonyl,alkylaminoalkylcarbonyl, dialkylaminoalkylcarbonyl,heterocyclylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, alkylsulfoxide,alkylsulfoxidealkyl, alkylsulfonyl and alkylsulfonealkyl; R² representsH, halo, alkyl, heterocyclyl, alkoxy, cycloalkyloxy, heterocyclyloxy,carbonyl, alkylcarbonyl, aminocarbonyl, hydroxycarbonyl,heterocyclylcarbonyl, alkylsulfoxide, alkylsulfonyl, aminosulfonyl,heterocyclylsulfonyl, alkylsulfonimidoyl, carbonylamino, sulfonylamino,or alkylsulfonealkyl; said substituents being optionally substituted byone or more substituent selected from oxo, halo, hydroxy, cyano, alkyl,alkenyl, aldehyde, heterocyclylalkyl, hydroxyalkyl, dihydroxyalkyl,hydroxyalkylaminoalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl,(heterocyclyl)(alkyl)aminoalkyl, heterocyclyl, heteroaryl,alkylheteroaryl, alkyne, alkoxy, amino, dialkylamino,aminoalkylcarbonylamino, aminocarbonylalkylamino,(aminocarbonylalkyl)(alkyl)amino, alkenylcarbonylamino, hydroxycarbonyl,alkyloxycarbonyl, aminocarbonyl, aminoalkylaminocarbonyl,alkylaminoalkylaminocarbonyl, dialkylaminoalkylaminocarbonyl,heterocyclylalkylaminocarbonyl, (alkylaminoalkyl)(alkyl)aminocarbonyl,alkylaminoalkylcarbonyl, dialkylaminoalkylcarbonyl,heterocyclylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, alkylsulfoxide,alkylsulfoxidealkyl, alkylsulfonyl and alkylsulfonealkyl; or R^(1′) andR^(2′) form together with the atoms to which they are attached a 5- or6-membered aryl ring, a 5- or 6-membered heteroaryl ring, a 5- or6-membered cycloalkyl ring or a 5- or 6-membered heterocyclyl ring;optionally substituted by one or more substituent selected from oxo,halo, hydroxy, cyano, alkyl, alkenyl, aldehyde, heterocyclylalkyl,hydroxyalkyl, dihydroxyalkyl, hydroxyalkylaminoalkyl, aminoalkyl,alkylaminoalkyl, dialkylaminoalkyl, (heterocyclyl)(alkyl)aminoalkyl,heterocyclyl, heteroaryl, alkylheteroaryl, alkyne, alkoxy, amino,dialkylamino, aminoalkylcarbonylamino, aminocarbonylalkylamino,(aminocarbonylalkyl)(alkyl)amino, alkenylcarbonylamino, hydroxycarbonyl,alkyloxycarbonyl, aminocarbonyl, aminoalkylaminocarbonyl,alkylaminoalkylaminocarbonyl, dialkylaminoalkylaminocarbonyl,heterocyclylalkylaminocarbonyl, (alkylaminoalkyl)(alkyl)aminocarbonyl,alkylaminoalkylcarbonyl, dialkylaminoalkylcarbonyl,heterocyclylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, alkylsulfoxide,alkylsulfoxidealkyl, alkylsulfonyl and alkylsulfonealkyl; R^(3′) isabsent when X² is N; or when X² is C, R′ represents H or halo; R^(4′)represents H or halo; and R^(5′) represents H or halo.
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 17. The method of claim 9, wherein the cancer is selectedfrom the group consisting of breast, carcinoid, cervical, colorectal,endometrial, glioma, head and neck, liver, lung, melanoma, ovarian,pancreatic, prostate, renal, gastric, thyroid and urothelial cancers.18. The method of claim 9, wherein the cancer is selected from breastcancer, prostate cancer, melanoma, and solid tumor.
 19. The method ofclaim 9, wherein the administration of the compound of Formula (I), or apharmaceutically acceptable salt thereof, is to be administered priorto, concomitantly, or subsequent to the checkpoint inhibitor.